Mechanistic basis for decreased antimicrobial susceptibility in a clinical isolate ofNeisseria gonorrhoeaepossessing a mosaic-likemtrefflux pump locus

Abstract

AbstractRecent reports suggest that mosaic-like sequences within themtr(multipletransferableresistance) efflux pump locus ofNeisseria gonorrhoeaelikely originating from commensalNeisseria sp.by transformation can increase the ability of gonococci to resist structurally diverse antimicrobials. Thus, acquisition of numerous nucleotide changes within themtrRgene encoding the transcriptional repressor (MtrR) of themtrCDEefflux pump-encoding operon or overlapping promoter region for both along with those that cause amino acid changes in the MtrD transporter protein were recently reported to decrease gonococcal susceptibility to numerous antimicrobials, including azithromycin (Azi) (Wadsworthet al.2018. MBio. doi.org/10.1128/mBio.01419-18). We performed detailed genetic and molecular studies to define the mechanistic basis for why such strains can exhibit decreased susceptibility to MtrCDE antimicrobial substrates including Azi. We report that a strongcis-acting transcriptional impact of a single nucleotide change within the -35 hexamer of themtrCDEpromoter as well gain-of-function amino acid changes at theC-terminal region of MtrD can mechanistically account for the decreased antimicrobial susceptibility of gonococci with a mosaic-likemtrlocus.IMPORTANCEHistorically, after introduction of an antibiotic for treatment of gonorrhea, strains ofN. gonorrhoeaeemerge that display clinical resistance due to spontaneous mutation or acquisition of resistance genes. Genetic exchange between members of theNeisseriagenus occurring by transformation can cause significant changes in gonococci that impact the structure of an antibiotic target or expression of genes involved in resistance. The results presented herein provide a framework for understanding how mosaic-like DNA sequences from commensalNeisseriathat recombine within the gonococcalmtrefflux pump locus function to decrease bacterial susceptibility to antimicrobials including antibiotics used in therapy of gonorrhea.