Introduction The resistance to extended-spectrum cephalosporins (ESCs), which is the only remaining antibiotic in many regions for treatment of gonorrhoea, expressed by certain strains of Neisseria gonorrhoeae is a major public concern worldwide. The first “superbug” reported in Japan was referred to H041, which was found to have high level resistance to ESCs and most other available antibiotics. Non-beta-lactamase resistance of gonococci to beta-lactam antibiotics requires several chromosomal mutations including a promoter mutation (single bp deletion in the mtrR promoter) that results in over-expression of the MtrCDE efflux. This promoter mutation results in loss of production of MtrR, which is the transcriptional repressor of mtrCDE., and is present in HO41. Here we investigated the possibility of reverting the resistant HO41 to be susceptible to β-lactam antibiotics by expressing MtrR and dampening the MtrCDE efflux pump.
Methods MtrR was ectopically expressed in HO41 (named as SC4) and confirmed to be functional by western blot and qRT-PCR analyses. HO41 and SC4 were compared for their susceptibility to antibiotics in laboratory media and in the presence of ME180 cervical epithelial with or without IPTG induction.
Results In both laboratory media and in ME180 cell culture, we found that expression of MtrR in SC4 (HO41 mtrR+) decreased mtrCDE gene expression and increased gonococcal susceptibility to beta-lactam antibiotics. Importantly, MtrR-mediated repression of mtrCDE decreased the MIC of penicillin to a level below the MIC breakpoint recommended clinical treatment dose.
Conclusion We demonstrate the MtrR-mediated dampening of mtrCDE can greatly increase gonococcal susceptibility to penicillin. Thus, novel adjunctive therapeutics that decrease levels of MtrCDE may allow for the return of penicillin as an option for treating otherwise resistant strains of gonococci.
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