The survival of bacteria in toxic environments is facilitated by intrinsic and acquired genes. One chromosomal region, the multiple antibiotic resistance chromosomal (mar) locus, is induced by a number of structurally unrelated compounds and by low pH. It provides resistance to antibiotics, disinfectants, organic solvents, and oxidative stress. The MarA transcriptional activator regulates a diverse group of genes comprising the Mar regulon. MarR represses the marRAB operon locus. The investigators propose to further investigate the mar locus and the mar regulon. Purification of MarR and MarA has been accomplished. Studies are proposed to determine the functional domains of MarR (repressor) and MarA (activator). For structural determination, X-ray crystallography and 2-D NMR studies will be performed. Since MarR and MarA are members of large protein families, work on these proteins should impact other areas of bacterial ecology and metabolism. They shall identify further mar-regulated (mlr) genes and their functions. Additional conditions which induce the mar operon or its targets will be sought. These results will enhance our understanding of the role of this complex regulon in adaptation of the bacterial cell to its environment. The functioning of the E. coli MarA protein in Mycobacterium smegmatis and the discovery of M. smegmatis Mar mutants has prompted a search for functional marA homologs in this genus. The frequency of Mar mutants in the environment will be observed to complement findings of Mar mutants among clinical E. coli isolates. The role that the mar locus plays (e.g., in quinolone resistance), when transiently expressed upon induction by salicylate, will be investigated. As bacteria emerge increasingly with multiple drug resistance, the role of regulatory loci such as mar in producing drug resistance has become of greater interest. Studies of the mar locus and its regulon will improve general understanding of how bacteria sense and respond to different environmental signals and allow identification of similar response systems in other bacteria of importance to public health.
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