The MtrCDE efflux pump of Neisseria gonorrhoeae exports a wide range of antimicrobial compounds that the gonococcus encounters at mucosal surfaces during colonization and infection. Here, we evaluate the role of this efflux pump system in strain FA1090 in human male urethral infection with a Controlled Human Infection Model. Using the strategy of competitive multi-strain infection with wild-type FA1090 and an isogenic mutant strain that does not contain a functional MtrCDE pump, we found that the presence of the efflux pump during human experimental infection did not confer a competitive advantage. This finding is in contrast to previous findings in female mice, which demonstrated that gonococci of strain FA19 lacking a functional MtrCDE pump had a significantly reduced fitness compared to the wild type strain in the lower genital tract of female mice. We conducted competitive infections in female mice with FA19 and FA1090 strains, including mutants that do not assemble a functional Mtr efflux pump, demonstrating the fitness advantage provided byt the MtrCDE efflux pump during infection of mice is strain dependent. Our data indicate that new gonorrhea treatment strategies targeting the MtrCDE efflux pump functions may not be universally efficacious in naturally occurring infections. Owing to the equal fitness of FA1090 strains in men, our experiments unexpectedly demonstrated the likely presence of an early colonization bottleneck of N. gonorrhoeae in the human male urethra.
Trial registration: Clinicaltrials.gov NCT03840811 .