Snyder, Lori, Ukachukwu, Faith [Contributor], Calder, Alan [Contributor], Rafiq, Afshan [Contributor], Horsburgh, Emily [Contributor], Jorge, Erik [Contributor], Sookdawar, Chetna [Contributor], Anwar, Sadaf [Contributor], Siwoku, Opeoluwa [Contributor] and Sriskantharajah, Vajiharan [Contributor] (2020) Antimicrobial fatty acids to combat antibiotic resistant 'Neisseria gonorrhoeae' infections. In: British Society for Antimicrobial Chemotherapy Conference 2020; cancelled due to COVID-19. (Unpublished)

Abstract

Background: Neisseria gonorrhoeae, causing gonorrhoea and rapidly progressing eye infections,have developed resistances to all of the antibiotics that are used clinically to treat it. It is imperative that new treatments are developed.Objectives: Fatty acid-based treatment options are being explored for development to preserve sight in the face of antimicrobial resistance.Research Question: Can fatty acids rapidly kill N. gonorrhoeae without causing ocular irritation?Design and Methodology: Antimicrobial fatty acids and their derivatives were assessed via agar diffusion and log reduction assay, both in GC broth and artificial tear fluid. Successful candidates killed at least 4 log10in 2 minutes in artificial tear fluid. These candidates were tested for ocular irritation using in vitro assays. To assess the potential for resistance to develop, cultures werepreviouslygrown for 20 passages in sublethal concentrations of the top candidate in an ‘evolve and resequence’experiment and the final MIC was determined.No resistance or genomic changes indicative of resistance was observed.Ocular formulation options have been investigated for stability and release of the drug, as well as shelf-life.Potential for development of vaginal formulations have been investigated through repeating log reduction assays in artificial vaginal fluid and mucosal irritation in vitro assays.Results: Novel drug candidates were shown to rapidly kill N. gonorrhoeae, to remain active in artificial tear fluid,artificial vaginal fluid, and to be non-irritating in ocular and mucosal irritation assays.Gonococci grown in sublethal concentrations of the lead candidate have been unable to achieve resistance. Further, analysis of genomic changes during exposure did not reveal mutationscharacteristic of the development of resistance.To develop thelead antimicrobial into a viable treatment option for use in cases of antibiotic resistant gonococcal ophthalmia neonatorumand adult eye infections, preformulation studies were conducted.Different formulationswere assessed to determine the best formulation for drug activity, stability, and long-term storage.Vaginal preparation development to combat cervical gonococcal infection is ongoing. Discussion: We have developed a promising prophylaxis and treatment for gonococcal eye infections, in both adults and neonates, which is able to rapidly kill N. gonorrhoeae without causing irritation. We have made promising progress toward a topical treatment for cervical N. gonorrhoeae infections in women.Conclusion: Fatty acids and their derivatives are a promising avenue for future antimicrobial treatment, due to their rapid killing, lack of irritation, and multiple modes of action on bacterial cells.

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