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]; [5], [6], [7]
  Pneumonia [ICD-11: CA40]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [4]
• 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]

• Resistant Disease: Anaerobic bacterial infection [ICD-11: 1A00-1A09]
• Molecule Alteration: Expression; Up-regulation
• 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.

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 2C (PBP2C) [4]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: jk0412 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Disk diffusion assay; Microdilution assay; E-Test assay
• Mechanism Description: Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp2c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole.

Key Molecule: Penicillin-binding protein 2C (PBP2C) [4]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: cu1571 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Disk diffusion assay; Microdilution assay; E-Test assay
• Mechanism Description: Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp5c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole.

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) [8]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.L421P
• 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) [5], [6], [7]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S
• 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) [5], [6], [7]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• 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) [5], [6], [7]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.V316T
• 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]

• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Molecule Alteration: Expression; Inherence
• 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: Exploration of the role of the penicillin binding protein 2c (Pbp2c) in inducible beta-lactam resistance in Corynebacteriaceae. Front Microbiol. 2024 May 9;15:1327723.
• Ref 5: 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 6: 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 7: 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 8: 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.