Disease Information

General Information of the Disease (ID: DIS00015)

• Name: Gonorrhea
• ICD: ICD-11: 1A70

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 8 drug(s) in total

Cefdinir

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [1]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S
• Resistant Drug: Cefdinir
• 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) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• Resistant Drug: Cefdinir
• 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) [2], [3], [4]

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

Cefditoren

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [1]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S
• Resistant Drug: Cefditoren
• 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) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• Resistant Drug: Cefditoren
• 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) [2], [3], [4]

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

Cefixime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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.A311V
• Resistant Drug: Cefixime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.T316P
• Resistant Drug: Cefixime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.A311V+p.T316P
• Resistant Drug: Cefixime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.T483S
• Resistant Drug: Cefixime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.T483S+p.A311V+p.T316P
• Resistant Drug: Cefixime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

Cefotiam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S
• Resistant Drug: Cefotiam
• 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) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• Resistant Drug: Cefotiam
• 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) [2], [3], [4]

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

Cefpodoxime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Probable peptidoglycan D,D-transpeptidase PenA (PENA) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S
• Resistant Drug: Cefpodoxime
• 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) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• Resistant Drug: Cefpodoxime
• 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) [2], [3], [4]

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

Ceftriaxone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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.A311V
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.T316P
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.A311V+p.T316P
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.T483S
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

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.T483S+p.A311V+p.T316P
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae FA19; 528352
• In Vitro Model: Neisseria gonorrhoeae FA6140; 528353
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: The penA gene,which encodes penicillin-binding protein 2 (PBP2), from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance.Tthree novel mutations, A311V, V316P, and T483S, that, when incorporated into the mosaic penA35 allele, are responsible for essentially all of the additional resistance conferred by penA41. Two of these mutations, A311V and T316P, are located near the active-site nucleophile Ser310, in a region previously shown to harbor mutations that increase resistance, whereas the remaining mutation, T483S, is in a different location in the structure of PBP2, where it may interact with the Beta-lactam carboxylate.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Type IV pilus biogenesis and competence protein PilQ (PILQ) [8]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G666K
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae PR100; 485
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Antibiotic resistance mediated by penC is the result of a Glu-666 to Lys missense mutation in the pilQ gene that interferes with the formation of the SDS-resistant high-molecular-mass PilQ secretin complex, disrupts piliation, and decreases transformation frequency by 50-fold.

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [9], [10]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.E91G
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae isolates; 485
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Fluoroquinolones block DNA replication by inhibiting the enzymes DNA gyrase (topoisomerase II) and topoisomerase IV. DNA gyrase catalyzes the untwisting of DNA molecules during DNA replication, and consists of two type A subunits and two type B subunits encoded by gyrA and gyrB genes. Topoisomerase IV consists of two type C subunits and two type E subunits encoded by parC and parE genes.GyrA S91F, D95G/D95A and ParC E91G amino acid substitutions mediate high fluoroquinolone resistance in the analyzed kenyan GC.

Key Molecule: DNA gyrase subunit A (GYRA) [9], [10]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.S91F+p.D95G/D95A
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae isolates; 485
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Fluoroquinolones block DNA replication by inhibiting the enzymes DNA gyrase (topoisomerase II) and topoisomerase IV. DNA gyrase catalyzes the untwisting of DNA molecules during DNA replication, and consists of two type A subunits and two type B subunits encoded by gyrA and gyrB genes. Topoisomerase IV consists of two type C subunits and two type E subunits encoded by parC and parE genes.GyrA S91F, D95G/D95A and ParC E91G amino acid substitutions mediate high fluoroquinolone resistance in the analyzed kenyan GC.

Penicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 1A (PBP1A) [11]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.L421P
• Resistant Drug: Penicillin
• 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) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S
• Resistant Drug: Penicillin
• 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) [2], [3], [4]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Molecule Alteration: Missense mutation; p.G545S+p.I312M
• Resistant Drug: Penicillin
• 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) [2], [3], [4]

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

References

• Ref 1: Positive selection in penicillin-binding proteins 1a, 2b, and 2x from Streptococcus pneumoniae and its correlation with amoxicillin resistance development. Infect Genet Evol. 2008 May;8(3):331-9. doi: 10.1016/j.meegid.2008.02.001. Epub 2008 Feb 14.
• Ref 2: 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 3: 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 4: 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 5: Reduced susceptibility to ceftriaxone in Neisseria gonorrhoeae is associated with mutations G542S, P551S and P551L in the gonococcal penicillin-binding protein 2. J Antimicrob Chemother. 2010 Aug;65(8):1615-8. doi: 10.1093/jac/dkq187. Epub 2010 May 28.
• Ref 6: High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012 Mar;56(3):1273-80. doi: 10.1128/AAC.05760-11. Epub 2011 Dec 12.
• Ref 7: Identification of amino acids conferring high-level resistance to expanded-spectrum cephalosporins in the penA gene from Neisseria gonorrhoeae strain H041. Antimicrob Agents Chemother. 2013 Jul;57(7):3029-36. doi: 10.1128/AAC.00093-13. Epub 2013 Apr 15.
• Ref 8: The penC mutation conferring antibiotic resistance in Neisseria gonorrhoeae arises from a mutation in the PilQ secretin that interferes with multimer stability. Mol Microbiol. 2005 Sep;57(5):1238-51. doi: 10.1111/j.1365-2958.2005.04752.x.
• Ref 9: Molecular epidemiology of drug-resistant Neisseria gonorrhoeae in Russia (Current Status, 2015). BMC Infect Dis. 2016 Aug 9;16:389. doi: 10.1186/s12879-016-1688-7.
• Ref 10: gyrA and parC mutations in fluoroquinolone-resistant Neisseria gonorrhoeae isolates from Kenya. BMC Microbiol. 2019 Apr 8;19(1):76. doi: 10.1186/s12866-019-1439-1.
• Ref 11: 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.