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Antimicrobial Agents and Chemotherapy, November 2008, p. 3915-3921, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00330-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones{triangledown}

Nadezhda German,1,{dagger} Muhammad Malik,2,{dagger} Jonathan D. Rosen,1 Karl Drlica,2 and Robert J. Kerns1*

Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, Iowa,1 Public Health Research Institute, New Jersey Medical School, UMDNJ, 225 Warren St., Newark, New Jersey2

Received 10 March 2008/ Returned for modification 15 June 2008/ Accepted 22 August 2008

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 10x 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.

* Corresponding author. Mailing address: Division of Medicinal and Natural Products Chemistry, University of Iowa, 115 S. Grand Ave., S321 Pharmacy Bldg., Iowa City, IA 52242. Phone: (319) 335-8800. Fax: (319) 335-8766. E-mail: robert-kerns{at}uiowa.edu

{triangledown} Published ahead of print on 2 September 2008.

{dagger} N.G. and M.M. contributed equally to this study.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3915-3921, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00330-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pan, X.-S., Gould, K. A., Fisher, L. M. (2009). Probing the Differential Interactions of Quinazolinedione PD 0305970 and Quinolones with Gyrase and Topoisomerase IV. Antimicrob. Agents Chemother. 53: 3822-3831 [Abstract] [Full Text]  


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