The Center for Adaptation Genetics and Drug Resistance at Tufts University School of Medicine. Stuart B. Levy, M.D., Director

Current and Ongoing Projects:

The Multiple Antibiotic Resistance / Adaptational Response (Mar) regulon - Year 27
Principal Investigator: Stuart B. Levy, M.D.
Co-PI: Laura McMurry, Ph.D.

A chromosomal regulatory protein 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) as well as infectivity of the organism. Overexpression of the marRAB operon, through mutations in marR or the promoter marO or by chemical inactivation of MarR, leads to increased drug resistance and other phenotypes. Removal of the locus decreases 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

  • George, A.M. and S.B. Levy (1983) A gene in the major co-transductional gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline, chloramphenicol and other antibiotics. J. Bacteriol. 155:541-548.

  • 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.

  • Cohen, S.P., H. Hachler, and S.B. Levy (1993) Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli.J. Bacteriol. 175:1484-1492.

  • 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.

  • 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.

  • 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.

  • 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

  • Nicoloff, H., V. Perreten, L. McMurry and S.B. Levy (2006). Role for tandem duplication and Lon protease in the AcrAB-TolC dependent multiple antibiotic resistance (Mar) phenotype in an Escherichia coli mutant without mutations in marRAB or acrRAB. J. Bacteriol. 188: 4413-4423.

  • Casaz, P., L.K. Garrity-Ryan, D. McKenney, C. Jackson, S.B. Levy, S.K. Tanaka and M.N. Alekshun (2006). MarA, SoxS, and Rob function as virulence factors in an Escherichia coli murine model of ascending pyelonephritis. Microbiology. 152:3643-3650.

  • Nicoloff, H., V. Perreten and S.B. Levy (2007). Increased genome instability in Escherichia coli lon mutants: relation to emergence of multiple antibiotic resistant (Mar) mutants caused by insertion sequence elements and large tandem genomic amplifications. Antimicrob. Agents Chemother. 51:1293-1303

  • Roberts, R., B. Hota, I. Ahmad, R.D. Scott II, S.D. Foster, F. Abbasai, S. Schabowski, L.M. Kampe, G.G. Viavrella, M. Supino, J. Naples, R. Cordell, S.B. Levy, R.A. Weinstein (2009) Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Inf Dis 49:1175 1184.

  • Warner, D and S.B. Levy (2010) Different effects of transcriptional regulators marA, soxS and rob on susceptibility of Escherichia coli to cationic antimicrobial peptides (CAMPs): Rob-dependent CAMP induction of the marRAB operon. Microbiology 156:570-578

  • Ruiz, C and S.B. Levy (2010) Many chromosomal genes modulate MarA-mediated multidrug resistance in Escherichia coli. Antimicrob Agents Chemother 54:2125-2134

  • Grier, M.C., L.K. Garrity-Ryan, V.J. Bartlett, K.A. Klausner, P.J. Donovan, C. Dudley, M.N. Alekshun, S.K. Tanaka, M.P. Draper, S.B. Levy (2010) N-Hydroxybenzimidazole inhibitors of ExsA MAR transcription factor in Pseudomonas aeruginosa: In vitro anti- virulence activity and metabolic stability. Bioorg Med Chem Lett 3380-3383.

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