Importance of the gonococcal MtrCDE efflux pump system in decreasing bacterial susceptibility to zoliflodacin: implications for future clinical treatment of gonorrhea

Vollständiger Abstract

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ABSTRACT The continued emergence and spread of Neisseria gonorrhoeae strains expressing clinical resistance to ceftriaxone (CRO) have stimulated the discovery of new antibiotics to treat gonococcal infections. As the MtrCDE efflux pump system has been linked to the ability of gonococci to develop resistance to multiple antibiotics (e.g., beta-lactams and macrolides), we studied whether it could diminish gonococcal susceptibility to a recently Food and Drug Administration (FDA)-approved antibiotic (zoliflodacin [ZOL]). ZOL recognizes DNA gyrase differently from other antibiotics and will likely be used in the future to treat uncomplicated urogenital tract infections that are refractory to cure by CRO. Herein, we provide evidence that mutations impacting mtrCDE gene expression or MtrCDE efflux activity can decrease gonococcal ZOL susceptibility. Moreover, these activities add to resistance levels afforded by a resistance mutation in gyrB . Hence, the accumulation of mutations in gyrB and mtr genes may negatively impact the future clinical efficacy of ZOL. IMPORTANCE The newly Food and Drug Administration (FDA)-approved antibiotic zoliflodacin (ZOL) will likely soon be used worldwide to treat gonococcal infections that are refractory to cure with the sole remaining antibiotic used in empiric monotherapy, ceftriaxone (CRO). Here, we find that the level of gonococcal susceptibility to ZOL is linked to expression and function of the MtrCDE efflux pump. This suggests that the future use of this new antibiotic will be challenged by mutations that are already present in clinical strains, as well as by mutations in a ZOL target gene ( gyrB ). Based on our collective observations and to extend the duration of ZOL in treating gonorrhea, we propose that future work should be devoted to developing adjunctive therapies that diminish its export by the MtrCDE efflux pump system.