Drug Information

Drug (ID: DG00252) and It's Reported Resistant Information

• Name: Penicillin
• Synonyms: Cillin; Pentids; 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; 3,3-Dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (Phenylmethyl)penicillin; 7005-30-3; NSC131815; (Phenylmethyl)penicillinic acid; 3,3-dimethyl-7-oxo-6-((phenylacetyl)amino)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; AC1L1DHC; AC1Q5UVJ; Penicilline G sodium salt; Oprea1_713794; Oprea1_861345; CHEMBL300052; SCHEMBL2109546; CTK2H5530
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Anaerobic bacterial infection [ICD-11: 1A09]; [2], [3]
  Gonorrhea [ICD-11: 1A70]; [4], [5], [6]
  Pneumonia [ICD-11: CA40]; [1]
• Target: Bacterial Penicillin binding protein (Bact PBP); NOUNIPROTAC; [1]
• Formula: C16H18N2O4S
• IsoSMILES: CC1(C(N2C(S1)C(C2=O)NC(=O)CC3=CC=CC=C3)C(=O)O)C
• InChI: 1S/C16H18N2O4S/c1-16(2)12(15(21)22)18-13(20)11(14(18)23-16)17-10(19)8-9-6-4-3-5-7-9/h3-7,11-12,14H,8H2,1-2H3,(H,17,19)(H,21,22)
• InChIKey: JGSARLDLIJGVTE-UHFFFAOYSA-N
• PubChem CID: 2349
• TTD Drug ID: D0R1BD
• DrugBank ID: DB01053

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Anaerobic bacterial infection [ICD-11: 1A00-1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Anaerobic bacterial infection [ICD-11: 1A00-1A09]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Acidaminococcus fermentans RYC-MR95; 905
• In Vitro Model: Acidaminococcus fermentans RYC4093; 905
• In Vitro Model: Acidaminococcus fermentans RYC4356; 905
• In Vitro Model: Escherichia coli RYC1000; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: A. intestini is the first Gram-negative coccus with demonstrated resistance to beta-lactam antibiotics. The reference genome of the A. intestini strain RyC-MR95, which was isolated from a perianal abscess of a European male diabetic patient, contains the aci1 gene, which encodes the ACI-1 class A beta-lactamase that confers resistance to penicillins and extended-spectrum cephalosporins.

Gonorrhea [ICD-11: 1A70]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 1A (PBP1A) [7]

• Molecule Alteration: Missense mutation; p.L421P
• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae 0387; 485
• In Vitro Model: Neisseria gonorrhoeae 2227; 485
• In Vitro Model: Neisseria gonorrhoeae 3391; 485
• In Vitro Model: Neisseria gonorrhoeae 5611; 485
• In Vitro Model: Neisseria gonorrhoeae 9634; 485
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The ponA1 gene encodes PBP 1 containing a single amino acid mutation, Leu-421-Pro. This single amino acid mutation was present in all chromosomally mediated resistant N. gonorrhoeae (CMRNG) strains for which MICs of penicillin were >=1 ug/ml. PBP 1 harboring this point mutation (PBP 1*) had a three- to fourfold lower rate of acylation (k2/k') than wild-type PBP 1 with a variety of Beta-lactam antibiotics.

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [4], [5], [6]

• Molecule Alteration: Missense mutation; p.G545S
• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae isolates strain; 485
• In Vitro Model: Neisseria gonorrhoeae strain ATCC 49226; 485
• In Vitro Model: Neisseria gonorrhoeae strain ATCC 700825; 485
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in N. gonorrhoeae.

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [4], [5], [6]

• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae isolates strain; 485
• In Vitro Model: Neisseria gonorrhoeae strain ATCC 49226; 485
• In Vitro Model: Neisseria gonorrhoeae strain ATCC 700825; 485
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in N. gonorrhoeae.

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [4], [5], [6]

• Molecule Alteration: Missense mutation; p.G545S+p.V316T
• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae isolates strain; 485
• In Vitro Model: Neisseria gonorrhoeae strain ATCC 49226; 485
• In Vitro Model: Neisseria gonorrhoeae strain ATCC 700825; 485
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in N. gonorrhoeae.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [1]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• 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.

References

• Ref 1: Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004 Jan;48(1):15-22. doi: 10.1128/AAC.48.1.15-22.2004.
• Ref 2: ACI-1 from Acidaminococcus fermentans: characterization of the first beta-lactamase in Anaerobic cocci. Antimicrob Agents Chemother. 2000 Nov;44(11):3144-9. doi: 10.1128/AAC.44.11.3144-3149.2000.
• Ref 3: ACI-1 beta-lactamase is widespread across human gut microbiomes in Negativicutes due to transposons harboured by tailed prophages. Environ Microbiol. 2018 Jun;20(6):2288-2300. doi: 10.1111/1462-2920.14276. Epub 2018 Aug 7.
• Ref 4: Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2006 Nov;50(11):3638-45. doi: 10.1128/AAC.00626-06. Epub 2006 Aug 28.
• Ref 5: Resistance to Beta-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins. Antibiotics (Basel). 2016 Sep 28;5(4):35. doi: 10.3390/antibiotics5040035.
• Ref 6: Crystal structures of penicillin-binding protein 2 from penicillin-susceptible and -resistant strains of Neisseria gonorrhoeae reveal an unexpectedly subtle mechanism for antibiotic resistance. J Biol Chem. 2009 Jan 9;284(2):1202-12. doi: 10.1074/jbc.M805761200. Epub 2008 Nov 4.
• Ref 7: Mutations in ponA, the gene encoding penicillin-binding protein 1, and a novel locus, penC, are required for high-level chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2002 Mar;46(3):769-77. doi: 10.1128/AAC.46.3.769-777.2002.