Drug Information

Drug (ID: DG00444) and It's Reported Resistant Information

• Name: Colistin
• Synonyms: Colistin sulphate; Polymyxin E; Colistin sulfate, nonsterile; Polymyxin E. Sulfate; Coly-Mycin M Parenteral (TN)
• Indication:
  In total 1 Indication(s)
  Glanders [ICD-11: 1B92]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (6 diseases)
  Bacteremia [ICD-11: MA15]; [2], [3]
  Bacterial meningitis [ICD-11: 1D02]; [2], [3]
  Lower respiratory tract infection [ICD-11: CA4Z]; [4]
  Pneumonia [ICD-11: CA40]; [2], [3]
  Salmonellosis [ICD-11: 1A09]; [1]
  Urinary tract infection [ICD-11: GC08]; [2], [3]
• Target: Bacterial Dihydropteroate synthetase (Bact folP); DHPS_ECOLI; [1]
• Formula: C52H98N16O13
• IsoSMILES: CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)[C@@H](NC1=O)CCN)CC(C)C)CC(C)C)CCN)CCN)[C@@H](C)O
• InChI: 1S/C52H98N16O13/c1-9-29(6)11-10-12-40(71)59-32(13-19-53)47(76)68-42(31(8)70)52(81)64-35(16-22-56)44(73)63-37-18-24-58-51(80)41(30(7)69)67-48(77)36(17-23-57)61-43(72)33(14-20-54)62-49(78)38(25-27(2)3)66-50(79)39(26-28(4)5)65-45(74)34(15-21-55)60-46(37)75/h27-39,41-42,69-70H,9-26,53-57H2,1-8H3,(H,58,80)(H,59,71)(H,60,75)(H,61,72)(H,62,78)(H,63,73)(H,64,81)(H,65,74)(H,66,79)(H,67,77)(H,68,76)/t29 ,30-,31-,32+,33+,34+,35+,36+,37+,38+,39-,41+,42+/m1/s1
• InChIKey: YKQOSKADJPQZHB-QNPLFGSASA-N
• PubChem CID: 5311054
• TTD Drug ID: D0K7NQ
• INTEDE ID: DR2644
• DrugBank ID: DB00803

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Salmonellosis [ICD-11: 1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Hydrolase (HYDE) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli NEB5alpha; 562
• Experiment for Molecule Alteration: In silico EMBOSS Transeq assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mcr-1 is a phosphoethanolamine transferase that modifies cell membrane lipid A head groups with a phosphoethanolamine residue, reducing affinity to colistin.

Bacterial meningitis [ICD-11: 1D02]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Multifunctional fusion protein (LPXA) [2], [3]

• Molecule Alteration: Frameshift mutation; c.90del
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.H159D
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; c.700C>T
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.G68D
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.391_421del
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.Q72K
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.76_78del
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.364_809del
• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• 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.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Transcriptional regulatory protein (PHOP) [5]

• Molecule Alteration: Missense mutation; p.D191Y
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• 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) [5]

• Molecule Alteration: Missense mutation; p.D191Y
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.90del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.H159D
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; c.700C>T
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.G68D
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.391_421del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.Q72K
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.76_78del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.364_809del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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.

ICD-16: Genitourinary system diseases

Urinary tract infection [ICD-11: GC08]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Transcriptional regulatory protein (PHOP) [5]

• Molecule Alteration: Missense mutation; p.D191Y
• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.90del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.H159D
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; c.700C>T
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.G68D
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.391_421del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.Q72K
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.76_78del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.364_809del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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.

ICD-21: Symptoms/clinical signs/unclassified clinical findings

Bacteremia [ICD-11: MA15]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Multifunctional fusion protein (LPXA) [2], [3]

• Molecule Alteration: Frameshift mutation; c.90del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.H159D
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; c.700C>T
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.G68D
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.391_421del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Missense mutation; p.Q72K
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.76_78del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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) [2], [3]

• Molecule Alteration: Frameshift mutation; c.364_809del
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• 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.

References

• Ref 1: Identification of Novel Mobilized Colistin Resistance Gene mcr-9 in a Multidrug-Resistant, Colistin-Susceptible Salmonella enterica Serotype Typhimurium Isolate. mBio. 2019 May 7;10(3):e00853-19. doi: 10.1128/mBio.00853-19.
• Ref 2: Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother. 2010 Dec;54(12):4971-7. doi: 10.1128/AAC.00834-10. Epub 2010 Sep 20.
• Ref 3: Biological cost of different mechanisms of colistin resistance and their impact on virulence in Acinetobacter baumannii. Antimicrob Agents Chemother. 2014;58(1):518-26. doi: 10.1128/AAC.01597-13. Epub 2013 Nov 4.
• Ref 4: Molecular Epidemiology and Drug Resistant Mechanism of Carbapenem-Resistant Klebsiella pneumoniae in Elderly Patients With Lower Respiratory Tract Infection .Front Public Health. 2021 May 20;9:669173. doi: 10.3389/fpubh.2021.669173. eCollection 2021. 10.3389/fpubh.2021.669173
• Ref 5: Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. Antimicrob Agents Chemother. 2015 May;59(5):2780-4. doi: 10.1128/AAC.05055-14. Epub 2015 Mar 2.