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Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility
Neisseria gonorrhoeae is an increasing public health threat due to its 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 that are resistant to all antibiotics...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765275/ https://www.ncbi.nlm.nih.gov/pubmed/34633841 http://dx.doi.org/10.1128/AAC.01542-21 |
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author | Evert, Benjamin J. Slesarenko, Valentin A. Punnasseril, Jilsy M. J. Taha, Zhan, Jian Zhou, Yaoqi Semchenko, Evgeny A. Seib, Kate L. |
author_facet | Evert, Benjamin J. Slesarenko, Valentin A. Punnasseril, Jilsy M. J. Taha, Zhan, Jian Zhou, Yaoqi Semchenko, Evgeny A. Seib, Kate L. |
author_sort | Evert, Benjamin J. |
collection | PubMed |
description | Neisseria gonorrhoeae is an increasing public health threat due to its 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 that are resistant to all antibiotics routinely used to treat the infection have emerged. 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 show 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. Cotreatment of bacteria with subinhibitory concentrations of the peptide led to 2- to 64-fold increases in susceptibility to erythromycin, azithromycin, ciprofloxacin, and/or ceftriaxone in N. gonorrhoeae strains FA1090, WHO K, WHO P, and WHO X. The cotreatment experiments with peptides P-MtrC1 and P-MtrE1 resulted in increased susceptibilities of WHO P and WHO X to azithromycin, ciprofloxacin, and ceftriaxone that were 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 may be developed for use as a dual treatment with existing antibiotics to treat multidrug-resistant gonococcal infections. |
format | Online Article Text |
id | pubmed-8765275 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-87652752022-01-24 Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility Evert, Benjamin J. Slesarenko, Valentin A. Punnasseril, Jilsy M. J. Taha, Zhan, Jian Zhou, Yaoqi Semchenko, Evgeny A. Seib, Kate L. Antimicrob Agents Chemother Experimental Therapeutics Neisseria gonorrhoeae is an increasing public health threat due to its 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 that are resistant to all antibiotics routinely used to treat the infection have emerged. 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 show 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. Cotreatment of bacteria with subinhibitory concentrations of the peptide led to 2- to 64-fold increases in susceptibility to erythromycin, azithromycin, ciprofloxacin, and/or ceftriaxone in N. gonorrhoeae strains FA1090, WHO K, WHO P, and WHO X. The cotreatment experiments with peptides P-MtrC1 and P-MtrE1 resulted in increased susceptibilities of WHO P and WHO X to azithromycin, ciprofloxacin, and ceftriaxone that were 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 may be developed for use as a dual treatment with existing antibiotics to treat multidrug-resistant gonococcal infections. American Society for Microbiology 2022-01-18 /pmc/articles/PMC8765275/ /pubmed/34633841 http://dx.doi.org/10.1128/AAC.01542-21 Text en Copyright © 2022 Evert et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Experimental Therapeutics Evert, Benjamin J. Slesarenko, Valentin A. Punnasseril, Jilsy M. J. Taha, Zhan, Jian Zhou, Yaoqi Semchenko, Evgeny A. Seib, Kate L. Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility |
title | Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility |
title_full | Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility |
title_fullStr | Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility |
title_full_unstemmed | Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility |
title_short | Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility |
title_sort | self-inhibitory peptides targeting the neisseria gonorrhoeae mtrcde efflux pump increase antibiotic susceptibility |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765275/ https://www.ncbi.nlm.nih.gov/pubmed/34633841 http://dx.doi.org/10.1128/AAC.01542-21 |
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