Journal article
Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones
Antimicrobial agents and chemotherapy, Vol.52(11), pp.3915-3921
09/02/2008
DOI: 10.1128/AAC.00330-08
PMCID: PMC2573108
PMID: 18765690
Abstract
A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the
gyr
+
(wild type) using isogenic strains of
Escherichia coli
. Dione features that lowered this ratio were a 3-amino group and C-7 ring structure (3-aminomethyl pyrrolidinyl < 3-aminopyrrolidinyl < diazobicyclo < 2-ethyl piperazinyl). The wild-type MIC was also lowered. With the most active derivative tested, many
gyrA
resistance mutant types were as susceptible as, or more susceptible than, wild-type cells. The most active 2,4-dione derivatives were also more active with two quinolone-resistant
gyrB
mutants than with wild-type cells. With respect to lethality, the most bacteriostatic 2,4-dione killed
E. coli
at a rate that was affected little by a
gyrA
resistance mutation, and it exhibited a rate of killing similar to its cognate fluoroquinolone at 10× the MIC. Population analysis with wild-type
E. coli
applied to agar showed that the mutant selection window for the most active 2,4-dione was narrower than that for the cognate fluoroquinolone or for ciprofloxacin. These data illustrate a new approach to guide early-stage antimicrobial selection. Use of antimutant activity (i.e., ratio of the antimicrobial MIC in a mutant strain to the antimicrobial MIC in a wild-type strain) as a structure-function selection criterion can be combined with traditional efforts aimed at lowering antimicrobial MICs against wild-type organisms to more effectively afford lead molecules with activity against both wild-type and mutant cells.
Details
- Title: Subtitle
- Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones
- Creators
- Nadezhda German - University of IowaMuhammad Malik - University of IowaJonathan D. Rosen - University of IowaKarl Drlica - University of IowaRobert J. Kerns - Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, Iowa, Public Health Research Institute, New Jersey Medical School, UMDNJ, 225 Warren St., Newark, New Jersey
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.52(11), pp.3915-3921
- Publisher
- American Society for Microbiology (ASM)
- DOI
- 10.1128/AAC.00330-08
- PMID
- 18765690
- PMCID
- PMC2573108
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Language
- English
- Date published
- 09/02/2008
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365882902771
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