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Antimicrobial Agents and Chemotherapy, December 2000, p. 3337-3343, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mutant Prevention Concentration as a Measure of Fluoroquinolone Potency against Mycobacteria†

Georg Sindelar,1 Xilin Zhao,1 Anthony Liew,1 Yuzhi Dong,1 Tao Lu,1 Jianfeng Zhou,1 John Domagala,2 and Karl Drlica1,*

Public Health Research Institute, New York, New York 10016,1 and Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, Michigan 481052

Received 17 April 2000/Returned for modification 24 July 2000/Accepted 11 September 2000

Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated. To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations. Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring. When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells. For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs. Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not. With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.

* Corresponding author. Mailing address: Public Health Research Institute, 455 First Ave., New York, NY 10016. Phone: (212) 578-0830. Fax: (212) 578-0804. E-mail: drlica{at}phri.nyu.edu.

dagger This is publication 74 from the Public Health Research Institute Tuberculosis Center.

Antimicrobial Agents and Chemotherapy, December 2000, p. 3337-3343, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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