A chromosomal regulatory locus in Escherichia coli, Shigella, Salmonella and other members of the Enterobacteriaceae simultaneously controls intrinsic levels of susceptibility to structurally different antibiotics (tetracyclines, chloramphenicols, penicillins, nalidixic acid, fluoroquinolones, etc.) and disinfectants (triclosan, quaternary ammonium compounds) and infectivity of the organism. Overexpression of the locus, through mutations in marR or marO or by chemical induction, leads to a variety of induced phenotypes. Absence of the locus leads to decreased virulence.
In the absence of an appropriate stimulus, two MarR dimers bind to marO to negatively regulate mar expression. Following exposure to a variety of structurally dissimilar compounds, acetylsalicylate (aspirin), plumbagin, paraquat, dinitrophenol, etc., one of several transcription factors (MarA, Rob, or SoxS) activates mar expression. Once synthesized MarA is then free to activate or repress a number of different genes on the E. coli chromosome. These genes encompass the mar regulon.
Present studies seek to define the basis for Mar regulatory activity, to identify the multiple target genes of this regulatory system, and the mechanisms of resistance involved.
Selected References
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- George, A.M. and S.B. Levy (1983) Amplifiable resistance to tetracycline, chloramphenicol and other antibiotics in Escherichia coli: identification of a non-plasmid mediated efflux system for tetracycline. J. Bacteriol 155:531-540.
- Hachler, H., S.P. Cohen, and S.B. Levy (1991)MarA: a regulated locus which controls expression of chromosomal multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 173:5532-5538.
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- Seoane, A. and S.B. Levy (1995)Characterization of MarR, the repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli.J. Bacteriol. 177:3414-3419.
- Goldman, J.D., D.G. White and S.B. Levy(1996) The multiple antibiotic resistance (mar) locus protects Escherichia coli from rapid cell killing by fluoroquinolones.Antimicrob.Agents Chemother. 40:1266-1269.
- Maneewannakul, K. and S.B. Levy (1996) Identification of Mar mutants among clinical isolates of quinolone resistant Escherichia coli.Antimicrob.Agents Chemother.40:1695-1698.
- Alekshun, M., and S.B. Levy (1997).Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob. Agents Chemother. 41:2067-2075.
- Moken, M.C., L.M. McMurry, and S. B. Levy. (1997) Selection of multiple antibiotic resistant (Mar) mutants of Escherichia coli by using the disinfectant pine oil: roles of the mar and acrAB loci.Antimicrob. Agents Chemother.41:2770-2772.
- White, D.G., K. Maneewannakul, E. von Hofe, M.Zillman, W. Eisenberg, A.K. Field, and S.B. Levy. (1997)Inhibition of the multiple antibiotic resistance (mar) operon in Escherichia coli by antisense DNA analogs.Antimicrob. Agents Chemother.41:2699-2704.McDermott, P., D.G. White, I. Podglajen, M. N. Alekshun, and S.B.Levy. (1998) Multidrug resistance following expression of the Escherichia coli marA gene in Mycobacterium smegmatis. J. Bacteriol. 180:2995-2998.
- McMurry, L.M., M. Oethinger and S.B. Levy. (1998) Overexpression of marA, soxS or acrAB produces resistance to triclosan in Escherichia coli.FEMS Microbiol. Lett. 166:305-309.
- Oethinger, M., I. Podglajen, W.V. Kern and S.B. Levy (1998) Overexpression of the regulatory marA of soxS gene contributes to fluoroquinolone resistance in clinical topoisomerase mutants of Escherichia coli.Antimicrob. Agents Chemother. 42:2089-2094.
- Barbosa, T. and S.B. Levy (2000) Differential expression of over 60 chromosomal genesin Escherichia coli by constitutive expression of MarA.J. Bacteriol. 182: 3467-3474.
- Oethinger, M., W.V. Kern, A.S. Jellen-Ritter, L.M. McMurry and S. B. Levy (2000) Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump.Antimicrob. Agents Chemother. 44:10-13.
- Alekshun, M.N., S.B. Levy, T.R. Mealy, B.A. Seaton, and J.F. Head (2001) The crystal structure of MarR a regulator of multiple antibiotic resistance, at 2.3A resolution. Nature Structural Biology 8: 710-714.
- Perreten, V., F.V. Schwarz, M. Teuber, and S.B. Levy (2001) Mdt(A), a new efflux protein conferring multiple antibiotic resistance in Lactococcus lactis and Escherichia coli.Antimicrob. Agents Chemother. 45: 1109-1114
- Wang, H., J.L. Dzink-Fox, M. Chen, and S.B. Levy (2001) Genetic characterization of high-level fluoroquinolone resistant clinical Eschericahia coli strains from China: role for acrR mutations.Antimicrob. Agnts. Chemother. 45: 1515-1521.
- Schneiders, T., T.M. Barbosa, L.M. McMurry & S.B. Levy (2004). The Escherichia coli transcriptional regulator MarA directly represses transcription of purA and hdeA.J. Biol. Chem. 279:9037-9042
- Schneiders, T. and S.B. Levy (2006). MarA mediated transcriptional repression of the rob promoter. J. Biol. Chem. (in press).
