Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa

被引:17
作者
Xu, Congjuan [1 ]
Liu, Huimin [2 ]
Pan, Xiaolei [1 ]
Ma, Zhenzhen [1 ]
Wang, Dan [1 ]
Zhang, Xinxin [1 ]
Zhu, Guangbo [2 ]
Bai, Fang [1 ]
Cheng, Zhihui [1 ]
Wu, Weihui [1 ]
Jin, Yongxin [1 ]
机构
[1] Nankai Univ, State Key Lab Med Chem Biol, Key Lab Mol Microbiol & Technol, Minist Educ,Dept Microbiol,Coll Life Sci, Tianjin, Peoples R China
[2] Nankai Univ, Tianjin Union Med Ctr, Affiliated Hosp, Tianjin, Peoples R China
来源
FRONTIERS IN MICROBIOLOGY | 2021年 / 11卷
基金
美国国家科学基金会;
关键词
Pseudomonas aeruginosa; ciprofloxacin resistance; mexS; gyrA; MexEF-OprN; MULTIDRUG EFFLUX SYSTEM; CYSTIC-FIBROSIS; MEXEF-OPRN; FLUOROQUINOLONE RESISTANCE; PUMP EXPRESSION; MEXAB-OPRM; MUTATIONS; SEQUENCE; GENE; PARC;
D O I
10.3389/fmicb.2020.598291
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
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页数:8
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