ArticleThe Journal of antimicrobial chemotherapy2024
In silico gepotidacin target mining among 33 213 global Neisseria gonorrhoeae genomes from 1928 to 2023 combined with gepotidacin MIC testing of 22 gonococcal isolates with different GyrA and ParC substitutions.
Article in The Journal of antimicrobial chemotherapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed.
- Stepwise evolution and clonal enrichment of gepotidacin resistance inAntimicrobial agents and chemotherapy · 2026Article
- Biology of novel LpxC inhibitors forMicrobiology spectrum · 2026Article
- In Vitro Activity of Zoliflodacin AgainstAntibiotics (Basel, Switzerland) · 2026Article
- Whole-genome characterization of seven multidrug-resistantFrontiers in microbiology · 2026Article
- Mechanism of Action of Gepotidacin: Well-Balanced Dual-Targeting againstACS infectious diseases · 2025Article
- The World Health Organization (WHO) Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) reports continuously high levels of ceftriaxone resistance across Viet Nam, 2024.The Lancet regional health. Western Pacific · 2025Article
- Management and prevention of Neisseria meningitidis and Neisseria gonorrhoeae infections in the context of evolving antimicrobial resistance trends.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Review
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11 authors.
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Abstract
objectivesThe novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations.
methodsWe examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site.
resultsGyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA.
conclusionsIn silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.
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