Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone

Dilek Ince; Xiamei Zhang; L Christine Silver; David C Hooper

doi:10.1128/AAC.46.11.3370-3380.2002

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Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone

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Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone

Dilek Ince, Xiamei Zhang, L Christine Silver and David C Hooper

Antimicrobial agents and chemotherapy, Vol.46(11), pp.3370-3380

11/2002

DOI: 10.1128/AAC.46.11.3370-3380.2002

PMCID: PMC128724

PMID: 12384338

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Abstract

We determined the target enzyme interactions of garenoxacin (BMS-284756, T-3811ME), a novel desfluoroquinolone, in Staphylococcus aureus by genetic and biochemical studies. We found garenoxacin to be four- to eightfold more active than ciprofloxacin against wild-type S. aureus. A single topoisomerase IV or gyrase mutation caused only a 2- to 4-fold increase in the MIC of garenoxacin, whereas a combination of mutations in both loci caused a substantial increase (128-fold). Overexpression of the NorA efflux pump had minimal effect on resistance to garenoxacin. With garenoxacin at twice the MIC, selection of resistant mutants (<7.4 x 10(-12) to 4.0 x 10(-11)) was 5 to 6 log units less than that with ciprofloxacin. Mutations inside or outside the quinolone resistance-determining regions (QRDR) of either topoisomerase IV, or gyrase, or both were selected in single-step mutants, suggesting dual targeting of topoisomerase IV and gyrase. Three of the novel mutations were shown by genetic experiments to be responsible for resistance. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that garenoxacin had similar activity against topoisomerase IV and gyrase (50% inhibitory concentration, 1.25 to 2.5 and 1.25 micro g/ml, respectively), and although its activity against topoisomerase IV was 2-fold greater than that of ciprofloxacin, its activity against gyrase was 10-fold greater. This study provides the first genetic and biochemical data supporting the dual targeting of topoisomerase IV and gyrase in S. aureus by a quinolone as well as providing genetic proof for the expansion of the QRDRs to include the 5' terminus of grlB and the 3' terminus of gyrA.

Fluoroquinolones

Staphylococcus aureus - genetics

Gene Expression Regulation, Enzymologic - drug effects

Staphylococcus aureus - enzymology

Anti-Infective Agents - pharmacology

Ciprofloxacin - pharmacology

DNA Gyrase - biosynthesis

Mutation - genetics

Quinolones

Microbial Sensitivity Tests

DNA Gyrase - genetics

Topoisomerase II Inhibitors

Alleles

Cloning, Molecular

DNA Topoisomerase IV - antagonists & inhibitors

Plasmids - drug effects

Plasmids - genetics

DNA Topoisomerase IV - genetics

Indoles

Drug Resistance, Bacterial - genetics

Staphylococcus aureus - drug effects

Details

Title: Subtitle: Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone
Creators: Dilek Ince - Division of Infectious Disease and Medical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696, USA
Xiamei Zhang
L Christine Silver
David C Hooper
Resource Type: Journal article
Publication Details: Antimicrobial agents and chemotherapy, Vol.46(11), pp.3370-3380
DOI: 10.1128/AAC.46.11.3370-3380.2002
PMID: 12384338
PMCID: PMC128724
NLM abbreviation: Antimicrob Agents Chemother
ISSN: 0066-4804
eISSN: 1098-6596
Grant note: R01 AI023988 / NIAID NIH HHS R01 AI23988 / NIAID NIH HHS
Language: English
Date published: 11/2002
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094753402771

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