The Gram-negative human pathogen Neisseria gonorrhoeae has progressively developed resistance to antibiotic monotherapies, and recent failures of dual-drug therapy have heightened concerns that strains resistant to all available antibiotics will begin circulating globally. Targeting bacterial cell wall assembly has historically been effective at treating infections with N. gonorrhoeae, but as the effectiveness of β-lactams (including cephalosporins) are challenged by increasing resistance, research has expanded into compounds that target the numerous other enzymes with roles in peptidoglycan metabolism. One example is the dithiazoline compound JNJ-853346 (DTZ), which inhibits the activity of an E. coli serine protease L,D-carboxypeptidase (LdcA). Recently, the characterization of an LdcA homolog in N. gonorrhoeae revealed localization and activity differences from the characterized E. coli LdcA, prompting us to explore the effectiveness of DTZ against N. gonorrhoeae. We found that DTZ is effective at inhibiting N. gonorrhoeae in all growth phases, unlike the specific stationary-phase inhibition seen in E. coli. Surprisingly, DTZ does not inhibit gonococcal LdcA enzyme activity, nor is DTZ sensitivity significantly decreased in ldcA mutants. While effective against numerous N. gonorrhoeae strains, including recent multi-drug resistant isolates, DTZ is much less effective at inhibiting growth of the commensal species Lactobacillus gasseri. DTZ treatment during co-infections of epithelial cells resulted in significant lowering of gonococcal burden and IL-8 secretion without significantly impacting recovery of viable L. gasseri. This selective toxicity presents a possible pathway for the use of DTZ as an effective anti-gonococcal agent at concentrations that do not impact vaginal commensals.
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