Drug Information

Drug (ID: DG00062) and It's Reported Resistant Information

• Name: Piperacillin
• Synonyms: PIPC; Peperacillin; Peracin; Pipercillin; Pipracil; Pipril; PIPERACILLIN SODIUM; Piperacillin Monosodium Salt; Piperacillin anhydrous; Cl-227193; Peracin (TN); Piperacillin (INN); Piperacillin (anhydrous); Pipracil, Piper; T-1220; Zobactin (TN); (2S,5R,6R)-6-[[(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S,5R,6R)-6-{[(2R)-2-{[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino}-2-phenylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S-(2alpha,5alpha,6beta(S*)))-6-(((((4-Ethyl-2,3-dioxopiperazin-1-yl)carbonyl)amino)phenylacetyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid; 4-ethyl-2,3-dioxopiperazine carbonyl ampicillin; 6-(D-(-)-alpha-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)phenylacetamido)penicillanicacid; 6beta-{(2R)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carboxamido]-2-phenylacetamido}-2,2-dimethylpenam-3alpha-carboxylic acid
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [3]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [4]
  Pneumonia [ICD-11: CA40]; [5]
• Target: Bacterial Penicillin binding protein (Bact PBP); NOUNIPROTAC; [1]
• Formula: C23H27N5O7S
• IsoSMILES: CCN1CCN(C(=O)C1=O)C(=O)N[C@H](C2=CC=CC=C2)C(=O)N[C@H]3[C@@H]4N(C3=O)[C@H](C(S4)(C)C)C(=O)O
• InChI: 1S/C23H27N5O7S/c1-4-26-10-11-27(19(32)18(26)31)22(35)25-13(12-8-6-5-7-9-12)16(29)24-14-17(30)28-15(21(33)34)23(2,3)36-20(14)28/h5-9,13-15,20H,4,10-11H2,1-3H3,(H,24,29)(H,25,35)(H,33,34)/t13-,14-,15+,20-/m1/s1
• InChIKey: IVBHGBMCVLDMKU-GXNBUGAJSA-N
• PubChem CID: 43672
• ChEBI ID: CHEBI:8232
• TTD Drug ID: D04ZAH
• VARIDT ID: DR00857
• INTEDE ID: DR2410
• DrugBank ID: DB00319

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Key Molecule: Beta-lactamase (BLA) [2], [6]

• Molecule Alteration: Missense mutation; p.D240G
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli Gre-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The first extended-spectrum Beta-lactamase (ESBL) of the CTX-M type (MEN-1/CTX-M-1) was reported at the beginning of the 1990s.CTX-M-27 differed from CTX-M-14 only by the substitution D240G and was the third CTX-M enzyme harbouring this mutation after CTX-M-15 and CTX-M-16. The Gly-240-harbouring enzyme CTX-M-27 conferred to Escherichia coli higher MICs of ceftazidime (MIC, 8 versus 1 mg/L) than did the Asp-240-harbouring CTX-M-14 enzyme.

Key Molecule: Beta-lactamase (BLA) [2], [7], [8]

• Molecule Alteration: Missense mutation; p.D240G
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Key Molecule: Metallo-beta-lactamase (VIM1) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Key Molecule: Beta-lactamase (BLA) [2], [9]

• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Citrobacter freundii strain 2524/96; 546
• In Vitro Model: Citrobacter freundii strain 2525/96; 546
• In Vitro Model: Citrobacter freundii strain 2526/96; 546
• In Vitro Model: Escherichia coli strain 2527/96; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 Beta-lactamase.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [3]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Non-tuberculous mycobacteria infection [ICD-11: 1B21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: OXA-23 carbapenemase (BLA OXA-23) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cutaneous bacterial infection [ICD-11: 1B21.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii isolates; 470
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay; Agar dilution method assay
• Mechanism Description: The isolate was resistant to antibiotics other than ampicillin-sulbactam and colistin, suggesting drug resistance due to carbapenemase production by OXA-23.carbapenem resistance in the isolated carbapenem-resistant A. baumannii strain was at least partially conferred by bla OXA-23-like carbapenemase.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bcr/CflA family efflux transporter (BCML) [5]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• 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) [5]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• 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) [5]

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

References

• Ref 1: Precise insertion of antibiotic resistance determinants into Tn21-like transposons: nucleotide sequence of the OXA-1 beta-lactamase gene. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7378-82. doi: 10.1073/pnas.84.21.7378.
• Ref 2: Identifying novel Beta-lactamase substrate activity through in silico prediction of antimicrobial resistance. Microb Genom. 2021 Jan;7(1):mgen000500. doi: 10.1099/mgen.0.000500.
• Ref 3: In70 of plasmid pAX22, a bla(VIM-1)-containing integron carrying a new aminoglycoside phosphotransferase gene cassette. Antimicrob Agents Chemother. 2001 Apr;45(4):1249-53. doi: 10.1128/AAC.45.4.1249-1253.2001.
• Ref 4: Daptomycin .J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. 10.1093/jac/dkx349
• Ref 5: Biochemical sequence analyses of GES-1, a novel class A extended-spectrum beta-lactamase, and the class 1 integron In52 from Klebsiella pneumoniae. Antimicrob Agents Chemother. 2000 Mar;44(3):622-32. doi: 10.1128/AAC.44.3.622-632.2000.
• Ref 6: Effect of D240G substitution in a novel ESBL CTX-M-27. J Antimicrob Chemother. 2003 Jul;52(1):29-35. doi: 10.1093/jac/dkg256. Epub 2003 May 29.
• Ref 7: Plasmid-mediated extended-spectrum beta-lactamase (CTX-M-3 like) from India and gene association with insertion sequence ISEcp1. FEMS Microbiol Lett. 2001 Jul 24;201(2):237-41. doi: 10.1111/j.1574-6968.2001.tb10762.x.
• Ref 8: Biochemical analysis of the ceftazidime-hydrolysing extended-spectrum beta-lactamase CTX-M-15 and of its structurally related beta-lactamase CTX-M-3. J Antimicrob Chemother. 2002 Dec;50(6):1031-4. doi: 10.1093/jac/dkf240.
• Ref 9: Cefotaxime-resistant Enterobacteriaceae isolates from a hospital in Warsaw, Poland: identification of a new CTX-M-3 cefotaxime-hydrolyzing beta-lactamase that is closely related to the CTX-M-1/MEN-1 enzyme. Antimicrob Agents Chemother. 1998 Apr;42(4):827-32. doi: 10.1128/AAC.42.4.827.