Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus

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

doi:10.1128/AAC.47.1.274-282.2003

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Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus

Journal article

Open access

Peer reviewed

Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus

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

Antimicrobial agents and chemotherapy, Vol.47(1), pp.274-282

01/2003

DOI: 10.1128/AAC.47.1.274-282.2003

PMCID: PMC149033

PMID: 12499202

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Abstract

Gemifloxacin, a novel quinolone with potent activity against Staphylococcus aureus, was 8- to 16-fold more active against wild-type S. aureus than ciprofloxacin. The two- to fourfold increase in the MIC of gemifloxacin in genetically defined grlBA mutants and the twofold increase in a single gyrA mutant, supported by the low frequency of selection of resistant mutants at twice the MIC (7.4 x 10(-11) to 1.1 x 10(-10)), suggested similar targeting of the two enzymes by gemifloxacin. Dual mutations in both gyrase and topoisomerase IV caused a 64- to 128-fold increase in the MIC of gemifloxacin, similar to that seen with ciprofloxacin. Gemifloxacin also had similar activity in vitro against topoisomerase IV and gyrase purified from S. aureus (50% inhibitory concentrations of 0.25 and 0.31 micro g/ml, respectively). This activity was 10- to 20-fold higher than that of ciprofloxacin for topoisomerase IV and 33-fold higher than that for gyrase. In contrast to the in vitro findings, only topoisomerase IV mutants were selected in first-step mutants. Overexpression of the NorA efflux pump had a minimal effect on resistance to gemifloxacin, and a mutation in the promoter region of the gene for NorA was selected only in the sixth step of serial selection of mutants. Our data show that although gemifloxacin targets purified topoisomerase IV and gyrase similarly in vitro, topoisomerase IV is the preferred target in the bacteria. Selection of novel resistance mutations in grlA requires further expansion of quinolone-resistance-determining regions, and their study may provide increased insight into enzyme-quinolone interactions.

Fluoroquinolones

Staphylococcus aureus - genetics

DNA Topoisomerases - classification

Staphylococcus aureus - enzymology

Anti-Infective Agents - pharmacology

DNA Topoisomerases - drug effects

DNA Topoisomerases - genetics

Microbial Sensitivity Tests

Gemifloxacin

Plasmids - genetics

Mutation

Drug Resistance, Bacterial - genetics

Staphylococcus aureus - drug effects

Naphthyridines - pharmacology

Details

Title: Subtitle: Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus
Creators: Dilek Ince - Division of Infectious Diseases 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.47(1), pp.274-282
DOI: 10.1128/AAC.47.1.274-282.2003
PMID: 12499202
PMCID: PMC149033
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: 01/2003
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094667502771

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