Abstract

Multiple antibiotic resistance is becoming a more frequent observation in clinical isolates throughout the world. A chromosomal regulatory locus called mar in E. coli and other enterobacteriaceae confers resistance to a variety of antibiotics when overexpressed. This kind of resistance has been found in E. coli clinical isolates from several countries. The proposed studies are designed to purify and define functionally the regulatory proteins of two divergent operons in the mar locus and to determine genes in the mar regulon that are targets of these proteins and that produce the Mar phenotype. The marRAB operon encodes MarR, a repressor of transcription, and MarA and MarB, putative activators of distant loci. Component genes will be cloned, purified as fusion proteins and tested for function. Electrophoresis will assist in identifying proteins involved in the Mar system. Potential DNA sequences for the regulatory proteins will be identified. Undefined resistance mechanisms for chloramphenicol, beta-lactam antibiotics and rifampicin will be studied. The frequency of mar operon mutations will be examined, as will the possible existence of similar systems in Pseudomonas aeruginosa. Homologous loci in other chromosomally resistant organisms such as the mycobacteria will be sought.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
9R01GM051661-11A1
Application #
2190336
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1980-09-30
Project End
1998-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111

  Publications

Schneiders, Thamarai; Barbosa, Teresa M; McMurry, Laura M et al. (2004) The Escherichia coli transcriptional regulator MarA directly represses transcription of purA and hdeA. J Biol Chem 279:9037-42
Bina, Xiaowen; Perreten, Vincent; Levy, Stuart B (2003) The periplasmic protein MppA requires an additional mutated locus to repress marA expression in Escherichia coli. J Bacteriol 185:1465-9
Schneiders, T; Amyes, S G B; Levy, S B (2003) Role of AcrR and ramA in fluoroquinolone resistance in clinical Klebsiella pneumoniae isolates from Singapore. Antimicrob Agents Chemother 47:2831-7
Koutsolioutsou, A; Martins, E A; White, D G et al. (2001) A soxRS-constitutive mutation contributing to antibiotic resistance in a clinical isolate of Salmonella enterica (Serovar typhimurium). Antimicrob Agents Chemother 45:38-43
Perreten, V; Schwarz, F V; Teuber, M et al. (2001) Mdt(A), a new efflux protein conferring multiple antibiotic resistance in Lactococcus lactis and Escherichia coli. Antimicrob Agents Chemother 45:1109-14
Wang, H; Dzink-Fox, J L; Chen, M et al. (2001) Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations. Antimicrob Agents Chemother 45:1515-21
Alekshun, M N; Kim, Y S; Levy, S B (2000) Mutational analysis of MarR, the negative regulator of marRAB expression in Escherichia coli, suggests the presence of two regions required for DNA binding. Mol Microbiol 35:1394-404
Oethinger, M; Kern, W V; Jellen-Ritter, A S et al. (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 44:3-Oct
Kern, W V; Oethinger, M; Jellen-Ritter, A S et al. (2000) Non-target gene mutations in the development of fluoroquinolone resistance in Escherichia coli. Antimicrob Agents Chemother 44:814-20
Barbosa, T M; Levy, S B (2000) Differential expression of over 60 chromosomal genes in Escherichia coli by constitutive expression of MarA. J Bacteriol 182:3467-74

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