Antibiotic resistance in microorganisms is now worldwide, in large part related to the spread of plasmids and acquisition of transposable resistances. Among many bacteria, however, newly discovered resistance determinants on the chromosome have emerged, generally to one, but occasionally to more than one group of antibiotics. We have recently described in E. coli a chromsomally-mediated amplifiable high-level resistance to six structurally different antibiotics with different target sites in mutants selected by growth in one drug. Several genes are involved in this """"""""multiple antibiotic resistance"""""""" (Mar) system; however, inactivation of one genetic locus, designated marA, results in complete loss of all resistances. The finding of cryptic chromosmal genes which express resistance and which have appeared and may emerge under clinical situations is of concern, particularly since we already know that the resistance mechanisms are at least in some cases distinct from those found on plasmids. Our proposed studies are aimed at understanding this new genetic system and these new mechanisms of resistance before they emerge as clinical problems. In addition, the bacterial Mar system has several striking characteristics in common with the amplifiable, multiresistance found in parasites and human and mammalian cancer cells in response to treatment with single chemotherapeutic drugs. Research on Mar may help to illuminate this general biologic response of cells to growth inhibitory agents. We shall use biochemical, molecular and genetic studies to examine the genes, gene products, and mechanisms for the multiple resistance phenotypes seen in the Mar mutants of E. coli. Such studies will involve 1) mapping and cloning the genes involved, 2) determining the genetic basis of the stepwise selection leading to high level resistance, 3) sequencing the marA locus, 4) sequencing some of the other genes involved in resistance, and 5) determining gene products and the biochemical and functional bases of the resistances. In order to gain insight into possible evolutionary links, we shall compare Mar-related chromosomal to resistance to those which we have already characterized on plasmids.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI016756-06A4
Application #
3126817
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1980-09-30
Project End
1993-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Alekshun, M N; Levy, S B (1997) Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob Agents Chemother 41:2067-75
Maneewannakul, K; Levy, S B (1996) Identification for mar mutants among quinolone-resistant clinical isolates of Escherichia coli. Antimicrob Agents Chemother 40:1695-8
Seoane, A S; Levy, S B (1995) Characterization of MarR, the repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli. J Bacteriol 177:3414-9
Seoane, A S; Levy, S B (1995) Identification of new genes regulated by the marRAB operon in Escherichia coli. J Bacteriol 177:530-5
Ariza, R R; Cohen, S P; Bachhawat, N et al. (1994) Repressor mutations in the marRAB operon that activate oxidative stress genes and multiple antibiotic resistance in Escherichia coli. J Bacteriol 176:143-8
McMurry, L M; George, A M; Levy, S B (1994) Active efflux of chloramphenicol in susceptible Escherichia coli strains and in multiple-antibiotic-resistant (Mar) mutants. Antimicrob Agents Chemother 38:542-6
Cohen, S P; Hachler, H; Levy, S B (1993) Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli. J Bacteriol 175:1484-92
Cohen, S P; Levy, S B; Foulds, J et al. (1993) Salicylate induction of antibiotic resistance in Escherichia coli: activation of the mar operon and a mar-independent pathway. J Bacteriol 175:7856-62
Cohen, S P; Yan, W; Levy, S B (1993) A multidrug resistance regulatory chromosomal locus is widespread among enteric bacteria. J Infect Dis 168:484-8
Seoane, A; Sabbaj, A; McMurry, L M et al. (1992) Multiple antibiotic susceptibility associated with inactivation of the prc gene. J Bacteriol 174:7844-7

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