Disease Information

General Information of the Disease (ID: DIS00126)

• Name: Pneumonia
• ICD: ICD-11: CA40

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 46 drug(s) in total

Acriflavine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Acriflavine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Amikacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [2]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [3]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Acinetobacter baumannii strain BM2580; 470
• In Vitro Model: Bacillus subtilis strain BS168; 1423
• Experiment for Molecule Alteration: Amino acid sequence comparison assay
• Mechanism Description: Resistance to aminogiycosides in Aeinetobaeter is widespread and is mainly the result of the production of enzymes which modify the antibiotics. The enzymes beiong to three ciasses: phosphotransferases (APH), acetyltransferases (AAC). A. baumahnii strain BM2580, a representative of one of these epidemics, was shown to synthesize a 3'-aminoglycoside phosphotransferase. Substrate specificity and DNA annealing studies indicated that the isozyme in A. baumannii was of a new type, designated APH(3')-VI.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Amoxicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 1A (PBP1A) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.S351A
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 1A (PBP1A) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.S575T
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 1A (PBP1A) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.N609D
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 1A (PBP1A) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.E512K
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T445A
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.E475G
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T488A
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.A591S
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.G596P
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.N605D
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.L608T
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.G618A
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.D624G
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.Q627E
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2B (PBP2B) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T629N
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T338A
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.E320K
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.Q552E
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.D311N
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.M343T
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.A491V
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.D506E
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T536I
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.V641I
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.L657I
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.A693V
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T703K
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.L710F
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.D740N
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.T745K
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.Q629K
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Key Molecule: Penicillin-binding protein 2X (PBP2X) [5]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.Q632T
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Correspondence discriminant assay
• Mechanism Description: The efficacy of Beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Benzylpenicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Benzylpenicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Benzylpenicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Benzylpenicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Cefalotin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Cefepime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Cefotaxime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Key Molecule: OmpK37 (OMPK37) [7]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Klebsiella pneumoniae strain CSUB10R; 573
• In Vitro Model: Klebsiella pneumoniae strain CSUB10S; 573
• In Vitro Model: Klebsiella pneumoniae strain LB4; 573
• In Vitro Model: Klebsiella pneumoniae strain LB66; 573
• In Vitro Model: Klebsiella pneumoniae strain SD8; 573
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Due to its porin deficiency, strain CSUB10R is more resistant to Beta-lactams than is parental strain CSUB10S. As expected, for k. pneumoniae CSUB10R expressing Ompk36 or Ompk35, the MICs reverted to values similar to those observed for strain CSUB10S.

Cefoxitin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Key Molecule: OmpK37 (OMPK37) [7]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Klebsiella pneumoniae strain CSUB10R; 573
• In Vitro Model: Klebsiella pneumoniae strain CSUB10S; 573
• In Vitro Model: Klebsiella pneumoniae strain LB4; 573
• In Vitro Model: Klebsiella pneumoniae strain LB66; 573
• In Vitro Model: Klebsiella pneumoniae strain SD8; 573
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Due to its porin deficiency, strain CSUB10R is more resistant to Beta-lactams than is parental strain CSUB10S. As expected, for k. pneumoniae CSUB10R expressing Ompk36 or Ompk35, the MICs reverted to values similar to those observed for strain CSUB10S.

Cefprozil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 2B (PBP2B) [8], [9], [10]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.T445A
• Resistant Drug: Cefprozil
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: MICs for and PBP affinities of the strains correlated with the changes found in the PBP active binding sites.The PBP2b T445-A substitution found in all PISP and PRSP and one PSSP has been found in all low-level Beta-lactam-resistant pneumococci examined.

Ceftazidime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae isolates; 573
• Experiment for Molecule Alteration: PCR and molecular characterization assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: CTX-M-55 is a novel ceftazidime-resistant CTX-M extended-spectrum Beta-lactamase, which reduced susceptibility.

Key Molecule: Beta-lactamase (BLA) [12]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterobacter cloacae strains ENLA-1; 550
• In Vitro Model: Escherichia coli strain ECAA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-2; 562
• In Vitro Model: Escherichia coli strain ECLA-4; 562
• In Vitro Model: Escherichia coli strain ECZK-1; 562
• In Vitro Model: Escherichia coli strain ECZP-1; 562
• In Vitro Model: Escherichia coli strain ECZU-1; 562
• In Vitro Model: Escherichia coli strain HK225f; 562
• In Vitro Model: Klebsiella pneumoniae strains KPAA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPBE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-3; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-5; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-9; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-11; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-12; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-13; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-9; 573
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-1; 149384
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-2; 149384
• Experiment for Molecule Alteration: Hybridization experiments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Of 60 strains with reduced susceptibility to expanded-spectrum cephalosporins which had been collected, 34 (24Klebsiella pneumoniae, 7Escherichia coli, 1Enterobacter cloacae, and 2Salmonella entericaserotypewien) hybridized with the intragenic blaSHVprobe. TheblaSHVgenes were amplified by PCR, and the presence ofblaSHV-ESBLwas established in 29 strains by restriction enzyme digests of the resulting 1,018-bp amplimers as described elsewhere. These results were confirmed by the nucleotide sequencing of all 34 amplimers. Five strains contained SHV non-ESBL enzymes.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Ceftobiprole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 2X (PBP2X) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; p.I371T
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Key Molecule: Penicillin-binding protein 2X (PBP2X) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; p.R384G
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Key Molecule: Penicillin-binding protein 2X (PBP2X) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; p.M400T
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Key Molecule: Penicillin-binding protein 2X (PBP2X) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; p.M339F
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Key Molecule: Penicillin-binding protein 2X (PBP2X) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; STMK motif p.M>F
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Key Molecule: Penicillin-binding protein 1A (PBP1A) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; STMK motif p.T >A +SRNVP motif p.P >T
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Key Molecule: Penicillin-binding protein 2B (PBP2B) [8], [9], [10]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Missense mutation; p.KTGTA motif p.A >G
• Resistant Drug: Ceftobiprole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae isolates; 1313
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Beta-Lactam resistance in S. pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from point mutations or mosaic genes. Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for Beta-lactam resistance among clinical isolates.

Ceftriaxone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae isolates; 573
• Experiment for Molecule Alteration: PCR and molecular characterization assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: CTX-M-55 is a novel ceftazidime-resistant CTX-M extended-spectrum Beta-lactamase, which reduced susceptibility.

Key Molecule: Beta-lactamase (BLA) [12]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterobacter cloacae strains ENLA-1; 550
• In Vitro Model: Escherichia coli strain ECAA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-2; 562
• In Vitro Model: Escherichia coli strain ECLA-4; 562
• In Vitro Model: Escherichia coli strain ECZK-1; 562
• In Vitro Model: Escherichia coli strain ECZP-1; 562
• In Vitro Model: Escherichia coli strain ECZU-1; 562
• In Vitro Model: Escherichia coli strain HK225f; 562
• In Vitro Model: Klebsiella pneumoniae strains KPAA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPBE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-3; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-5; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-9; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-11; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-12; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-13; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-9; 573
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-1; 149384
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-2; 149384
• Experiment for Molecule Alteration: Hybridization experiments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Of 60 strains with reduced susceptibility to expanded-spectrum cephalosporins which had been collected, 34 (24Klebsiella pneumoniae, 7Escherichia coli, 1Enterobacter cloacae, and 2Salmonella entericaserotypewien) hybridized with the intragenic blaSHVprobe. TheblaSHVgenes were amplified by PCR, and the presence ofblaSHV-ESBLwas established in 29 strains by restriction enzyme digests of the resulting 1,018-bp amplimers as described elsewhere. These results were confirmed by the nucleotide sequencing of all 34 amplimers. Five strains contained SHV non-ESBL enzymes.

Cephaloridine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cephaloridine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Cephaloridine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Cephaloridine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Chloramphenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Like CMLA1, this novel protein (CMLA4) likely conferred resistance to chloramphenicol by a nonenzymatic mechanism. Among the 207 bp upstream of cmlA4, only four nucleotide changes were identified, compared to the sequence found upstream of cmlA1 (data not shown). Downstream from cmlA4, an inverse core site (GCCCAAC) was part of a composite 59-be of 70 bp. This 59-be was almost 100% identical to the downstream region of cmlA1, except for one nucleotide change (T to C in cmlA4) at the last position (position 4,997).

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA gyrase subunit A (GYRA) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S843F (TCC-TTC)
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: An additional mutant obtained in vitro, BM4205-R3, displayed a higher level of fluoroquinolone resistance and had a mutation in gyrA leading to a Ser-84-Phe change.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae isolates; 573
• Experiment for Molecule Alteration: PCR and molecular characterization assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: CTX-M-55 is a novel ceftazidime-resistant CTX-M extended-spectrum Beta-lactamase, which reduced susceptibility.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Clarithromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [14]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clarithromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: One mechanism of macrolide resistance is via drug inactivation: enzymatic hydrolysis of the macrolactone ring catalyzed by erythromycin esterases, EreA and EreB.

Co-trimoxazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S37T
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [16]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.T55A
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocytis jirovecii strain; 42068
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: In these 5 resistance-fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation.

Key Molecule: Dihydrofolate reductase (DHFR) [16]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.P57S
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocytis jirovecii strain; 42068
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: In these 5 resistance-fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation.

Key Molecule: Dihydrofolate reductase (DHFR) [16]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.T55A+p.P57S
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocytis jirovecii strain; 42068
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: In these 5 resistance-fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation.

Colistin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Transcriptional regulatory protein (PHOP) [17]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Missense mutation; p.D191Y
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae kp75; 573
• In Vitro Model: Klebsiella pneumoniae ATCC 53153; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutated protein PhoP activates the transcription of the pmrHFIJkLM operon, the product of which leads to synthesis of L-amino-arabinose and ultimately to colistin resistance in k. pneumoniae.These modifications create a more positively charged lipopolysaccharide and thus reduce the affinity of LPS to positively charged polymyxins.

Key Molecule: Transcriptional regulatory protein (PHOP) [17]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Missense mutation; p.D191Y
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae kp75; 573
• In Vitro Model: Klebsiella pneumoniae ATCC 53153; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutated protein PhoP activates the transcription of the pmrHFIJkLM operon, the product of which leads to synthesis of L-amino-arabinose and ultimately to colistin resistance in k. pneumoniae.These modifications create a more positively charged lipopolysaccharide and thus reduce the affinity of LPS to positively charged polymyxins.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.90del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; p.H159D
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1844; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; c.700C>T
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1845; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; p.G68D
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1846; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.391_421del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; p.Q72K
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1848; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.76_78del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [18], [19]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.364_809del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Daunorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Daunorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Edetic acid

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase type 2 (BLAN1) [20]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Function; Inhibition
• Sensitive Drug: Edetic acid
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Molecular modeling assay
• Experiment for Drug Resistance: Double-disk diffusion test assay
• Mechanism Description: Disk diffusion and broth microdilution methods demonstrate that unithiol inhibits native MBLs NDM-1 and VIM-2 produced by carbapenem-resistant K. pneumoniae and P. aeruginosa bacterial strains.

Erythromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [14]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: One mechanism of macrolide resistance is via drug inactivation: enzymatic hydrolysis of the macrolactone ring catalyzed by erythromycin esterases, EreA and EreB.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [21]

• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Gentamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Gentamicin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [2]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Hydrocortisone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [22]

• Resistant Disease: Chronic inflammatory lung disease [ICD-11: CA40.Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Hydrocortisone
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: For therapeutic drugs to be effective at reducing the proinflammatory/cytotoxic potential of steroid resistant lymphocytes, glucocorticoids enter cells by overcoming membrane drug efflux pump P-glycoprotein-1 (Pgp1) and binding to the glucocorticoid receptor (GCR) in the cytoplasm. GCR must be bound to the molecular chaperones heat shock proteins (Hsp)70 and Hsp90 to acquire a high-affinity steroid binding conformation, and trafficked to the nucleus where engagement of histone deacetylases (HDACs), particularly HDAC2, results in the reduction of pro-inflammatory gene activation.

Kanamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [2]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [3]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Acinetobacter baumannii strain BM2580; 470
• In Vitro Model: Bacillus subtilis strain BS168; 1423
• Experiment for Molecule Alteration: Amino acid sequence comparison assay
• Mechanism Description: Resistance to aminogiycosides in Aeinetobaeter is widespread and is mainly the result of the production of enzymes which modify the antibiotics. The enzymes beiong to three ciasses: phosphotransferases (APH), acetyltransferases (AAC). A. baumahnii strain BM2580, a representative of one of these epidemics, was shown to synthesize a 3'-aminoglycoside phosphotransferase. Substrate specificity and DNA annealing studies indicated that the isozyme in A. baumannii was of a new type, designated APH(3')-VI.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Meropenem

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: OmpK37 (OMPK37) [7]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Klebsiella pneumoniae strain CSUB10R; 573
• In Vitro Model: Klebsiella pneumoniae strain CSUB10S; 573
• In Vitro Model: Klebsiella pneumoniae strain LB4; 573
• In Vitro Model: Klebsiella pneumoniae strain LB66; 573
• In Vitro Model: Klebsiella pneumoniae strain SD8; 573
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Due to its porin deficiency, strain CSUB10R is more resistant to Beta-lactams than is parental strain CSUB10S. As expected, for k. pneumoniae CSUB10R expressing Ompk36 or Ompk35, the MICs reverted to values similar to those observed for strain CSUB10S.

Norfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Novobiocin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Novobiocin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Paromomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [2]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Paromomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Pefloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Resistant Drug: Pefloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Resistant Drug: Pefloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Resistant Drug: Pefloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit A (GYRA) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S843F (TCC-TTC)
• Resistant Drug: Pefloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: An additional mutant obtained in vitro, BM4205-R3, displayed a higher level of fluoroquinolone resistance and had a mutation in gyrA leading to a Ser-84-Phe change.

Penicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [23]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Penicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae 11978; 573
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: The Beta-lactamase OXA-48 hydrolyzed imipenem at a high level.

Pentamidine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.D153V
• Resistant Drug: Pentamidine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Piperacillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Proflavine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Short-chain diamines transporter (PACE) [24]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Proflavine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Burkholderia cenocepacia HI2424; 95486
• In Vitro Model: Klebsiella pneumoniae 342; 573
• In Vitro Model: Pseudomonas syringae pv. Tomato strain DC3000; 323
• In Vitro Model: Vibrio parahaemolyticus strain; 670
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The novel AceI (Acinetobacter chlorhexidine efflux) protein from Acinetobacter baumannii that conferred resistance to the biocide chlorhexidine, via an active efflux mechanism. MIC analyses demonstrated that, like AceI, many of the homologs conferred resistance to chlorhexidine. Many of the AceI homologs conferred resistance to additional biocides, including benzalkonium, dequalinium, proflavine, and acriflavine.

Pyrimethamine/Sulfadoxine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.I158V+p.V79I
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.Y197L
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.T14A+p.P26Q
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.M52I+p.E63G+p.T144A+p.K171E
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S106P+p.E127G+p.R170G
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Ribostamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [2]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ribostamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Roxithromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [14]

• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Roxithromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: One mechanism of macrolide resistance is via drug inactivation: enzymatic hydrolysis of the macrolactone ring catalyzed by erythromycin esterases, EreA and EreB.

Sparfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Resistant Drug: Sparfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Resistant Drug: Sparfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Resistant Drug: Sparfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA gyrase subunit A (GYRA) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S843F (TCC-TTC)
• Resistant Drug: Sparfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: An additional mutant obtained in vitro, BM4205-R3, displayed a higher level of fluoroquinolone resistance and had a mutation in gyrA leading to a Ser-84-Phe change.

Tetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Key Molecule: Tetracycline efflux protein (TET41) [25]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Experiment for Molecule Alteration: DNA sequencing and protein and phylogenetic assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Tet 41 is a tetracycline-specific efflux pump, which lead to drug resistance.

Key Molecule: Tetracycline efflux proteintet(39) (TET39) [26]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter sp. LUH5605; 309867
• Experiment for Molecule Alteration: DNA multiple alignment assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet39 produces drug resistance through the action of nonspecific efflux pump.

Ticarcillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Klebsiella pneumoniae ORI-1 strain harbored a ca. 140-kb nontransferable plasmid, pTk1, that conferred an extended-spectrum cephalosporin resistance profile antagonized by the addition of clavulanic acid, tazobactam, or imipenem. The gene for GES-1 (Guiana extended-spectrum beta-lactamase) was cloned, and its protein was expressed in Escherichia coli DH10B, where this pI-5. 8 beta-lactamase of a ca. 31-kDa molecular mass conferred resistance to oxyimino cephalosporins (mostly to ceftazidime). GES-1 is weakly related to the other plasmid-located Ambler class A extended-spectrum beta-lactamases (ESBLs).

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Beta-Lactam MICs for k. pneumoniae ORI-1 and Escherichia coli DH10B harboring either the natural plasmid pTk1 or the recombinant plasmid pC1 were somewhat similar and might indicate the presence of an ESBL. In all cases, the ceftazidime MICs were higher than those of cefotaxime and aztreonam. Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [6]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Antagonism
• Sensitive Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli strain NCTC 50192; 562
• In Vitro Model: Klebsiella pneumoniae strain ORI-1; 573
• Experiment for Molecule Alteration: PCR and hybridization experiments assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Inhibition studies, as measured by IC50 values with benzylpenicillin as the substrate, showed that GES-1 was inhibited by clavulanic acid (5 uM) and tazobactam (2.5 uM) and strongly inhibited by imipenem (0.1 uM). Beta-Lactam MICs were always lowered by the addition of clavulanic acid or tazobactam, less so by sulbactam, and uncommonly by imipenem.

Triclosan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Triclosan
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Trimethoprim

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [4]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Trimethoprim
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Trimethoprim
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Unithiol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase type 2 (BLAN1) [20]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Function; Inhibition
• Sensitive Drug: Unithiol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Klebsiella pneumoniae strain 409; 573
• In Vitro Model: Klebsiella pneumoniae strain 410; 573
• Experiment for Molecule Alteration: Molecular modeling assay
• Experiment for Drug Resistance: Double-disk diffusion test assay
• Mechanism Description: Disk diffusion and broth microdilution methods demonstrate that unithiol inhibits native MBLs NDM-1 and VIM-2 produced by carbapenem-resistant K. pneumoniae and P. aeruginosa bacterial strains.

Imipenem

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [23]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae 11978; 573
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: The Beta-lactamase OXA-48 hydrolyzed imipenem at a high level.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: OmpK37 (OMPK37) [7]

• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Klebsiella pneumoniae strain CSUB10R; 573
• In Vitro Model: Klebsiella pneumoniae strain CSUB10S; 573
• In Vitro Model: Klebsiella pneumoniae strain LB4; 573
• In Vitro Model: Klebsiella pneumoniae strain LB66; 573
• In Vitro Model: Klebsiella pneumoniae strain SD8; 573
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Due to its porin deficiency, strain CSUB10R is more resistant to Beta-lactams than is parental strain CSUB10S. As expected, for k. pneumoniae CSUB10R expressing Ompk36 or Ompk35, the MICs reverted to values similar to those observed for strain CSUB10S.

Clinical Trial Drug(s) 1 drug(s) in total

Rhodamine 6G

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Rhodamine 6G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Discontinued Drug(s) 2 drug(s) in total

Bisbenzimide (Hoechst 33258)

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Bisbenzimide (Hoechst 33258)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

PD131628

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Resistant Drug: PD131628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Resistant Drug: PD131628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Resistant Drug: PD131628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA gyrase subunit A (GYRA) [13]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S843F (TCC-TTC)
• Resistant Drug: PD131628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: An additional mutant obtained in vitro, BM4205-R3, displayed a higher level of fluoroquinolone resistance and had a mutation in gyrA leading to a Ser-84-Phe change.

Investigative Drug(s) 6 drug(s) in total

4',6-Diamidino-2-phenylindole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: 4',6-Diamidino-2-phenylindole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Arylomycin C16

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Signal peptidase I (LEPB) [5], [27]

• Resistant Disease: Streptococcus pneumoniae infection [ICD-11: AA80.2]
• Molecule Alteration: Missense mutation; p.S29P
• Resistant Drug: Arylomycin C16
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus capitis isolates strain; 29388
• In Vitro Model: Staphylococcus caprae isolates strain; 29380
• In Vitro Model: Staphylococcus cohnii isolates strain; 29382
• In Vitro Model: Staphylococcus epidermidis isolates strain; 1282
• In Vitro Model: Staphylococcus haemolyticus isolates strain; 1283
• In Vitro Model: Staphylococcus hominis isolates strain; 1290
• In Vitro Model: Staphylococcus lugdunensis isolates strain; 28035
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: S. epidermidis evolves resistance to the arylomycins by mutating residue 29 of one of its two SPases, SpsIB, from Ser (Ser29) to Pro (Pro29).

Butirosina

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [2]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Butirosina
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Homidium bromide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Homidium bromide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Pyrimethamine/Atovaquone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [15]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Molecule Alteration: Missense mutation; p.S37T
• Resistant Drug: Pyrimethamine/Atovaquone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Tetraphenylphosphonium chloride

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [1]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetraphenylphosphonium chloride
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

References

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