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Antimicrobial Agents and Chemotherapy, July 2002, p. 2124-2131, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2124-2131.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

CmeABC Functions as a Multidrug Efflux System in Campylobacter jejuni

Jun Lin, Linda Overbye Michel, and Qijing Zhang*

Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio 44691

Received 27 December 2001/ Returned for modification 11 March 2002/ Accepted 10 April 2002

Campylobacter jejuni, a gram-negative organism causing gastroenteritis in humans, is increasingly resistant to antibiotics. However, little is known about the drug efflux mechanisms in this pathogen. Here we characterized an efflux pump encoded by a three-gene operon (designated cmeABC) that contributes to multidrug resistance in C. jejuni 81-176. CmeABC shares significant sequence and structural homology with known tripartite multidrug efflux pumps in other gram-negative bacteria, and it consists of a periplasmic fusion protein (CmeA), an inner membrane efflux transporter belonging to the resistance-nodulation-cell division superfamily (CmeB), and an outer membrane protein (CmeC). Immunoblotting using CmeABC-specific antibodies demonstrated that cmeABC was expressed in wild-type 81-176; however, an isogenic mutant (9B6) with a transposon insertion in the cmeB gene showed impaired production of CmeB and CmeC. Compared to wild-type 81-176, 9B6 showed a 2- to 4,000-fold decrease in resistance to a range of antibiotics, heavy metals, bile salts, and other antimicrobial agents. Accumulation assays demonstrated that significantly more ethidium bromide and ciprofloxacin accumulated in mutant 9B6 than in wild-type 81-176. Addition of carbonyl cyanide m-chlorophenylhydrazone, an efflux pump inhibitor, increased the accumulation of ciprofloxacin in wild-type 81-176 to the level of mutant 9B6. PCR and immunoblotting analysis also showed that cmeABC was broadly distributed in various C. jejuni isolates and constitutively expressed in wild-type strains. Together, these findings formally establish that CmeABC functions as a tripartite multidrug efflux pump that contributes to the intrinsic resistance of C. jejuni to a broad range of structurally unrelated antimicrobial agents.

* Corresponding author. Mailing address: Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University, 1680 Madison Ave., Wooster, OH 44691. Phone: (330) 263-3747. Fax: (330) 263-3677. E-mail: zhang.234{at}osu.edu.

Antimicrobial Agents and Chemotherapy, July 2002, p. 2124-2131, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2124-2131.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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