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Antimicrobial Agents and Chemotherapy, October 2001, p. 2703-2709, Vol. 45, No. 10
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.10.2703-2709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Enhancement of Fluoroquinolone Activity by C-8 Halogen and Methoxy Moieties: Action against a Gyrase Resistance Mutant of Mycobacterium smegmatis and a Gyrase-Topoisomerase IV Double Mutant of Staphylococcus aureus

Tao Lu,1 Xilin Zhao,1 Xinying Li,1 Alex Drlica-Wagner,1 Jian-Ying Wang,1 John Domagala,2 and Karl Drlica1,*

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

Received 4 December 2000/Returned for modification 10 January 2001/Accepted 6 July 2001

The increasing prevalence of antibiotic resistance among bacterial pathogens prompted a microbiological study of fluoroquinolone structure-activity relationships with resistant mutants. Bacteriostatic and bactericidal activities for 12 fluoroquinolones were examined with a gyrase mutant of Mycobacterium smegmatis and a gyrase-topoisomerase IV double mutant of Staphylococcus aureus. For both organisms C-8 halogen and C-8 methoxy groups enhanced activity. The MIC at which 99% of the isolates tested were inhibited (MIC99) was reduced three- to fivefold for the M. smegmatis mutant and seven- to eightfold for the S. aureus mutant by C-8 bromine, chlorine, and methoxy groups. With both organisms a smaller reduction in the MIC99 (two- to threefold) was associated with a C-8 fluorine moiety. In most comparisons with M. smegmatis the response to a C-8 substituent was similar (within twofold) for wild-type and mutant cells. In contrast, mutant S. aureus was affected more than the wild type by the addition of a C-8 substituent. C-8 halogen and methoxy groups also improved the ability to kill the two mutants and the respective wild-type cells when measured with various fluoroquinolone concentrations during an incubation period equivalent to four to five doubling times. Collectively these data help define a group of fluoroquinolones that can serve (i) as a base for structure refinement and (ii) as test compounds for slowing the development of fluoroquinolone resistance during infection of vertebrate hosts.

* 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.

Antimicrobial Agents and Chemotherapy, October 2001, p. 2703-2709, Vol. 45, No. 10
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.10.2703-2709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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