Self-inhibitory peptides targeting the Neisseria gonorrhoeae MtrCDE efflux pump increase antibiotic susceptibility.
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Author(s)
Evert, Benjamin J
Slesarenko, Valentin A
Punnasseril, Jilsy MJ
Taha
Zhan, Jian
Zhou, Yaoqi
Semchenko, Evgeny A
Seib, Kate L
Year published
2021
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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 ...
View more >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.
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View more >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.
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Journal Title
Antimicrobial Agents and Chemotherapy
Copyright Statement
© 2021 Evert et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Note
This publication has been entered as an advanced online version in Griffith Research Online.
Subject
Microbiology
Medical microbiology
Pharmacology and pharmaceutical sciences