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Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa
Treatment of infections by Pseudomonas aeruginosa is difficult due to its high intrinsic and acquired antibiotic resistance. Upon colonization in the human hosts, P. aeruginosa accumulates genetic mutations that confer the bacterium antibiotic resistance and ability to better live in the host enviro...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819972/ https://www.ncbi.nlm.nih.gov/pubmed/33488544 http://dx.doi.org/10.3389/fmicb.2020.598291 |
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author | Xu, Congjuan Liu, Huimin Pan, Xiaolei Ma, Zhenzhen Wang, Dan Zhang, Xinxin Zhu, Guangbo Bai, Fang Cheng, Zhihui Wu, Weihui Jin, Yongxin |
author_facet | Xu, Congjuan Liu, Huimin Pan, Xiaolei Ma, Zhenzhen Wang, Dan Zhang, Xinxin Zhu, Guangbo Bai, Fang Cheng, Zhihui Wu, Weihui Jin, Yongxin |
author_sort | Xu, Congjuan |
collection | PubMed |
description | Treatment of infections by Pseudomonas aeruginosa is difficult due to its high intrinsic and acquired antibiotic resistance. Upon colonization in the human hosts, P. aeruginosa accumulates genetic mutations that confer the bacterium antibiotic resistance and ability to better live in the host environment. Characterizing the evolutionary traits would provide important insights into the development of effective combinatory antibiotic therapies to cure P. aeruginosa infections. In this work, we performed a detailed analysis of the molecular mechanisms by which a clinical isolate (CSP18) yields a ciprofloxacin-resistant derivative (CRP42). Genomic DNA re-sequencing and RNAseq were carried out to compare the genomic mutational signature and transcriptional profiles between the two isolates. The results indicated that D87G mutation in GyrA, together with MexEF-OprN hyper-expression caused by F7S mutation in MexS, was responsible for the increased resistance to ciprofloxacin in the isolate CRP42. Further simulation of CRP42 by gene editing in CSP18 demonstrated that D87G mutation in GyrA rendered CSP18 a fourfold increase in minimum inhibitory concentration against ciprofloxacin, while F7S mutation in MexS conferred an additional eightfold increase. Our experimental results demonstrate for the first time that the clinically relevant F7S point mutation in MexS results in hyper-expression of the mexEF-oprN and thus confers P. aeruginosa resistance to ciprofloxacin. |
format | Online Article Text |
id | pubmed-7819972 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78199722021-01-23 Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa Xu, Congjuan Liu, Huimin Pan, Xiaolei Ma, Zhenzhen Wang, Dan Zhang, Xinxin Zhu, Guangbo Bai, Fang Cheng, Zhihui Wu, Weihui Jin, Yongxin Front Microbiol Microbiology Treatment of infections by Pseudomonas aeruginosa is difficult due to its high intrinsic and acquired antibiotic resistance. Upon colonization in the human hosts, P. aeruginosa accumulates genetic mutations that confer the bacterium antibiotic resistance and ability to better live in the host environment. Characterizing the evolutionary traits would provide important insights into the development of effective combinatory antibiotic therapies to cure P. aeruginosa infections. In this work, we performed a detailed analysis of the molecular mechanisms by which a clinical isolate (CSP18) yields a ciprofloxacin-resistant derivative (CRP42). Genomic DNA re-sequencing and RNAseq were carried out to compare the genomic mutational signature and transcriptional profiles between the two isolates. The results indicated that D87G mutation in GyrA, together with MexEF-OprN hyper-expression caused by F7S mutation in MexS, was responsible for the increased resistance to ciprofloxacin in the isolate CRP42. Further simulation of CRP42 by gene editing in CSP18 demonstrated that D87G mutation in GyrA rendered CSP18 a fourfold increase in minimum inhibitory concentration against ciprofloxacin, while F7S mutation in MexS conferred an additional eightfold increase. Our experimental results demonstrate for the first time that the clinically relevant F7S point mutation in MexS results in hyper-expression of the mexEF-oprN and thus confers P. aeruginosa resistance to ciprofloxacin. Frontiers Media S.A. 2021-01-08 /pmc/articles/PMC7819972/ /pubmed/33488544 http://dx.doi.org/10.3389/fmicb.2020.598291 Text en Copyright © 2021 Xu, Liu, Pan, Ma, Wang, Zhang, Zhu, Bai, Cheng, Wu and Jin. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Xu, Congjuan Liu, Huimin Pan, Xiaolei Ma, Zhenzhen Wang, Dan Zhang, Xinxin Zhu, Guangbo Bai, Fang Cheng, Zhihui Wu, Weihui Jin, Yongxin Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa |
title | Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa |
title_full | Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa |
title_fullStr | Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa |
title_full_unstemmed | Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa |
title_short | Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa |
title_sort | mechanisms for development of ciprofloxacin resistance in a clinical isolate of pseudomonas aeruginosa |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819972/ https://www.ncbi.nlm.nih.gov/pubmed/33488544 http://dx.doi.org/10.3389/fmicb.2020.598291 |
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