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Journal of Bacteriology, September 1998, p. 4686-4692, Vol. 180, No. 17
0021-9193/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Multidrug Efflux Pump AcrAB of Salmonella typhimurium Excretes Only Those beta -Lactam Antibiotics Containing Lipophilic Side Chains

Hiroshi Nikaido,* Marina Basina, Vy Nguyen, and Emiko Y. Rosenberg

Department of Molecular and Cell Biology, University of California, Berkeley, California 94708-3206

Received 9 April 1998/Accepted 29 June 1998

We found that the previously reported SS-B drug-supersusceptible mutant of Salmonella typhimurium (S. Sukupolvi, M. Vaara, I. M. Helander, P. Viljanen, and P. H. Mäkelä, J. Bacteriol. 159:704-712, 1984) had a mutation in the acrAB operon. Comparison of this mutant with its parent strain and with an AcrAB-overproducing strain showed that the activity of the AcrAB efflux pump often produced significant resistance to beta -lactam antibiotics in the complete absence of beta -lactamase. The effect of AcrAB activity on resistance was more pronounced with agents containing more lipophilic side chains, suggesting that such compounds were better substrates for this pump. This correlation is consistent with the hypothesis that only those molecules that become at least partially partitioned into the lipid bilayer of the cytoplasmic membrane are captured by the AcrAB pump. According to this mechanism, the pump successfully excretes even those beta -lactams that fail to traverse the cytoplasmic membrane, because these compounds are likely to become partitioned into the outer leaflet of the bilayer. Even the compounds with lipophilic side chains were shown to penetrate across the outer membrane relatively rapidly, if the pump was inactivated genetically or physiologically. The exclusion of such compounds, exemplified by nafcillin, from cells of the wild-type S. typhimurium was previously interpreted as the result of poor diffusion across the outer membrane (H. Nikaido, Biochim. Biophys. Acta 433:118-132, 1976), but it is now recognized as the consequence of efficient pumping out of entering antibiotics by the active efflux process.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, 229 Stanley Hall, University of California, Berkeley, CA 94720-3206. Phone: (510) 642-2027. Fax: (510) 643-9290. E-mail: nhiroshi{at}uclink4.berkeley.edu.

Journal of Bacteriology, September 1998, p. 4686-4692, Vol. 180, No. 17
0021-9193/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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