Emergence of a Potent Multidrug Efflux Pump Variant That Enhances Campylobacter Resistance to Multiple Antibiotics

Authors

Hong Yao, China Agricultural University
Zhangql Shen, China Agricultural University
Yang Wang, China Agricultural University
Fengru Deng, China Agricultural University
Dejun Liu, China Agricultural University
Gaowa Naren, China Agricultural University
Lel Dal, Iowa State University
Chih-Chia Su, Iowa State University
Bing Wang, University of Nebraska-LincolnFollow
Shaolin Wang, China Agricultural University
Congming Wu, China Agricultural University
Edward W. Yu, Iowa State University
Qijing Zhang, Iowa State University
Jianzhong Shen, China Agricultural University

Date of this Version

2016

Citation

Yao H, Shen Z, Wang Y, Deng F, Liu D, Naren G, Dai L, Su C, Wang B, Wang S, Wu C, Yu EW, Zhang Q, Shen J. 2016. Emergence of a potent multidrug efflux pump variant that enhances Campylobacter resistance to multiple antibiotics. mBio 7(5):e01543-16.

Comments

© 2016 Yao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Abstract

Bacterial antibiotic efflux pumps are key players in antibiotic resistance. Although their role in conferring multidrug resistance is well documented, the emergence of “super” efflux pump variants that enhance bacterial resistance to multiple drugs has not been reported. Here, we describe the emergence of a resistance-enhancing variant (named RE-CmeABC) of the predominant efflux pump CmeABC in Campylobacter, a major zoonotic pathogen whose resistance to antibiotics is considered a serious antibiotic resistance threat in the United States. Compared to the previously characterized CmeABC transporters, RECmeABC is much more potent in conferring Campylobacter resistance to antibiotics, which was shown by increased MICs and reduced intracellular accumulation of antibiotics. Structural modeling suggests that sequence variations in the drug-binding pocket of CmeB possibly contribute to the enhanced efflux function. Additionally, RE-CmeABC expands the mutant selection window of ciprofloxacin, enhances the emergence of antibiotic-resistant mutants, and confers exceedingly high-level resistance to fluoroquinolones, an important class of antibiotics for clinical therapy of campylobacteriosis. Furthermore, RE-CmeABC is horizontally transferable, shifts antibiotic MIC distribution among clinical isolates, and is increasingly prevalent in Campylobacter jejuni isolates, suggesting that it confers a fitness advantage under antimicrobial selection. These findings reveal a new mechanism for enhanced multidrug resistance and an effective strategy utilized by bacteria for adaptation to selection from multiple antibiotics.