The escalating problem of bacterial resistance to antibiotics calls for radical changes in the existing antibacterial therapies. One of the most promising approaches is the use of antibiotic potentiators, compounds that make bacterial cells hypersusceptible to antibiotics. The goal of the project is to identify multiple novel molecular targets for potentiators. This will be accomplished by isolating antibiotic hypersusceptibility mutations of Gram-negative bacteria, Acinetobacter and/or Escherichia coli. These mutations will specify bacterial proteins whose inhibition is likely to potentiate antimicrobial action of antibiotics. Antibiotic hypersusceptibility is a very difficult phenotype to select, and only few such mutations are known. We have designed and tested a novel genetic strategy for selection of hypersusceptibility mutations, termed SDR. Application of this strategy will identify multiple mutations increasing bacterial susceptibility to beta-lactams (ampicillin, ceftazidime, imipenem), translational inhibitors (erythromycin, linezolid, tetracycline, and chloramphenicol) and fluoroquinolone antibiotics (ciprofloxacin). The molecular mechanisms underlying the effects of the most interesting of these mutations will be analyzed. In addition to identifying promising targets for potentiators, the project will help unravel new aspects of the mechanism of action of antibiotics and new features of bacterial physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI049214-01A1
Application #
6431136
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
2002-02-15
Project End
2006-01-31
Budget Start
2002-02-15
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$324,599
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Vazquez-Laslop, Nora; Lee, Hyunwoo; Neyfakh, Alexander A (2006) Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J Bacteriol 188:3494-7
Lee, Hyunwoo; Vazquez-Laslop, Nora; Klyachko, Katya A et al. (2003) Isolation of antibiotic hypersusceptibility mutants of Acinetobacter spp. by selection for DNA release. Antimicrob Agents Chemother 47:1267-74