P1849 In vitro activities of gepotidacin, a novel triazaacenaphthylene topoisomerase IV and DNA gyrase inhibitor, against Gram-negative bacteria and Staphylococcus saprophyticus Shazad Mushtaq*1, Anna Vickers1, Zahra Sadouki1, Michelle Cole1, Helen Fifer1, Vivienne Donascimento1, Martin Day1, Elizabeth De Pinna1, Claire Jenkins1, Gauri Godbole1, Neil Woodford1

1 Public Health England, London, United Kingdom Background: Gepotidacin is a triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by binding to novel sites on DNA gyrase and topoisomerase IV. We evaluated its in-vitro activity against clinical bacterial isolates, including those with antibiotic resistance mechanisms of high international public health importance. Materials/methods: The panel comprised 511 Enterobacteriaceae enriched to include isolates with ESBLs, AmpC or carbapenemases; 55 Pseudomonas aeruginosa selected to include isolates with carbapenemases, ESBLs, or carbapenem resistance due to OprD loss and/or efflux; 60 Acinetobacter baumannii with carbapenemases; 95 Neisseria gonorrhoeae including those with resistance or reduced susceptibility to beta-lactams, ciprofloxacin, azithromycin, tetracycline or spectinomycin; and 51 Staphylococcus saprophyticus isolates. MICs were determined according to CLSI agar dilution guidelines. Results: Gepotidacin MICs for E. coli ranged ≤0.06-64mg/L, with 96.1% inhibited at 8mg/L. Shigella MICs ranged 0.125-8mg/L, with 95.6% inhibited at 2mg/L. Gepotidacin MICs ranged higher for Klebsiella, Enterobacter and Proteus, with MIC90s of 64, 32, and 32mg/L, respectively. Gepotidacin MICs for all Enterobacteriaceae tested were unrelated to levofloxacin resistance or to amino acid substitutions in the QRDRs of GyrA and ParC. Gepotidacin MIC90 for P. aeruginosa and A. baumannii were 32 and 64mg/L respectively, and were unrelated to levofloxacin resistance. Gepotidacin MICs for N. gonorrhoeae ranged ≤0.06-2mg/L, with 95.8% inhibited at 1mg/L, and were unaffected by ciprofloxacin resistance. MICs for all S. saprophyticus were ≤0.125mg/L.

Gepotidacin MIC mg/L ≤0.25 0.5 1 2 4 8 ≥16 MIC50 MIC90 E. coli (n=254) 4 22 56 92 37 33 10 2 8 Shigella (n=91) 14 18 36 19 3 1 1 2 Klebsiella (n=55) 1 6 14 34 16 64 Enterobacter (n=55) 1 3 12 7 32 16 32 Proteus (n=56) 3 4 11 9 10 19 8 32 P. aeruginosa (n=55) 1 2 4 18 15 15 8 32 A. baumannii (n=60) 7 53 32 64 N. gonorrhoeae (n=95) 79 6 6 4 0.25 1 S. saprophyticus (n=51) 51 ≤0.06 0.125

Conclusions: Gepotidacin was active in-vitro against N. gonorrhoeae (95.8% ≤1mg/L), and S. saprophyticus (100% ≤0.125mg/L). At 8mg/L, gepotidacin was active against drug resistant E. coli (96.1%) and Shigella (100%), but less active against other Gram-negative genera tested.

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