Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Congjuan, Liu, Huimin, Pan, Xiaolei, Ma, Zhenzhen, Wang, Dan, Zhang, Xinxin, Zhu, Guangbo, Bai, Fang, Cheng, Zhihui, Wu, Weihui, Jin, Yongxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
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
_version_ 1783639108397039616
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
work_keys_str_mv AT xucongjuan mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT liuhuimin mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT panxiaolei mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT mazhenzhen mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT wangdan mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT zhangxinxin mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT zhuguangbo mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT baifang mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT chengzhihui mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT wuweihui mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa
AT jinyongxin mechanismsfordevelopmentofciprofloxacinresistanceinaclinicalisolateofpseudomonasaeruginosa