Self-inhibitory peptides targeting the Neisseria gonorrhoeae MtrCDE efflux pump increase antibiotic susceptibility.

Abstract

Neisseria gonorrhoeae is an increasing public health threat due to rapidly rising incidence and antibiotic resistance. There are an estimated 106 million cases per year worldwide, there is no vaccine available to prevent infection, and N. gonorrhoeae strains have emerged that are resistant to all antibiotics routinely used to treat the infection. In many strains, antibiotic resistance is mediated by overexpression of the MtrCDE efflux pump, which enables the bacteria to transport toxic antibiotics out of the cell. Genetic mutations that inactivate MtrCDE have previously been shown to render resistant strains susceptible to certain antibiotics. Here we have shown that peptides rationally-designed to target and disrupt the activity of each of the three protein components of MtrCDE were able to increase the susceptibility of N. gonorrhoeae strains to antibiotics, in a dose-dependent manner and with no toxicity to human cells. Co-treatment of bacteria with subinhibitory concentrations of peptide led to 2-64 fold increases in the susceptibility to erythromycin, azithromycin, ciprofloxacin and/or ceftriaxone in N. gonorrhoeae strains FA1090, WHO K, WHO P and WHO X. The co-treatment experiments with peptides P-MtrC1 and P-MtrE1 resulted in increased susceptibility to azithromycin, ciprofloxacin and ceftriaxone in WHO P and WHO X that was of the same magnitude seen in MtrCDE mutants. P-MtrE1 was able to change the azithromycin resistance profile of WHO P from resistant to susceptible. Data presented here demonstrate that these peptides could be developed for use as a dual treatment with existing antibiotics to treat multidrug-resistant gonococcal infections.