Drug Information

Drug (ID: DG00121) and It's Reported Resistant Information

• Name: Ticarcillin
• Synonyms: TIPC; Ticarcilina; Ticarcilline; Ticarcillinum; Ticarcillin Supplement; Ticillin [veterinary]; BRL-2288; Ticarcilina[INN-Spanish]; Ticarcillin (INN); Ticarcillin [INN:BAN]; Ticarcilline [INN-French]; Ticarcillinum [INN-Latin]; Ticillin [veterinary] (TN); Timentin (TN); A-carboxy-3-thienylmethylpenicillin; Alpha-carboxy-3-thienylmethylpenicillin; (2S,5R,6R)-6-[[(2R)-3-hydroxy-3-oxo-2-thiophen-3-ylpropanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S,5R,6R)-6-{[(2R)-2-carboxy-2-(3-thienyl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S,5R,6R)-6-{[(2R)-2-carboxy-2-thiophen-3-ylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; 6beta-{[(2R)-2-carboxy-2-thiophen-3-ylacetyl]amino}-2,2-dimethylpenam-3alpha-carboxylic acid
• 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]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [4], [5], [6]
  Pneumonia [ICD-11: CA40]; [7]
• Target: Bacterial Penicillin binding protein (Bact PBP); NOUNIPROTAC; [1]
• Formula: C15H16N2O6S2
• IsoSMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)[C@@H](C3=CSC=C3)C(=O)O)C(=O)O)C
• InChI: 1S/C15H16N2O6S2/c1-15(2)9(14(22)23)17-11(19)8(12(17)25-15)16-10(18)7(13(20)21)6-3-4-24-5-6/h3-5,7-9,12H,1-2H3,(H,16,18)(H,20,21)(H,22,23)/t7-,8-,9+,12-/m1/s1
• InChIKey: OHKOGUYZJXTSFX-KZFFXBSXSA-N
• PubChem CID: 36921
• ChEBI ID: CHEBI:9587
• TTD Drug ID: D08USU
• INTEDE ID: DR2409
• DrugBank ID: DB01607

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

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.

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) [8]

• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Metallo-beta-lactamase NDM-4 (NDM4) [1]

• Molecule Alteration: Missense mutation; p.M154L
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli I5; 562
• 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: A clinical Escherichia coli isolate resistant to all Beta-lactams, including carbapenems, expressed a novel metallo-Beta-lactamase (MBL), NDM-4, differing from NDM-1 by a single amino acid substitution (Met154Leu). NDM-4 possessed increased hydrolytic activity toward carbapenems and several cephalosporins compared to that of NDM-1.

Key Molecule: Beta-lactamase (BLA) [6], [9]

• 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) [4], [5], [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 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.

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) [7]

• 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) [7]

• 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) [7]

• 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: NDM-4 metallo-Beta-lactamase with increased carbapenemase activity from Escherichia coli. Antimicrob Agents Chemother. 2012 Apr;56(4):2184-6. doi: 10.1128/AAC.05961-11. Epub 2012 Jan 17.
• 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: 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 5: 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 6: 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 7: 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 8: Characterization of OXA-181, a carbapenem-hydrolyzing class D beta-lactamase from Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011 Oct;55(10):4896-9. doi: 10.1128/AAC.00481-11. Epub 2011 Jul 18.
• Ref 9: 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.