Document Detail


Dual targeting of DNA gyrase and topoisomerase IV: target interactions of heteroaryl isothiazolones in Staphylococcus aureus.
MedLine Citation:
PMID:  17502409     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Heteroaryl isothiazolones (HITZs) are antibacterial agents that display excellent in vitro activity against Staphylococcus aureus. We recently identified a series of these compounds that show potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA). We report here the results of in vitro resistance studies that reveal potential underlying mechanisms of action. HITZs selected gyrA mutations exclusively in first-step mutants of wild-type S. aureus, indicating that in contrast to the case with most quinolones, DNA gyrase is the primary target. The compounds displayed low mutation frequencies (10(-9) to 10(-10)) at concentrations close to the MICs and maintained low MICs (< or =0.016 microg/ml) against mutants with single mutations in either gyrA or grlA (parC). These data suggested that HITZs possess significant inhibitory activities against target enzymes, DNA gyrase and topoisomerase IV. This dual-target inhibition was supported by low 50% inhibitory concentrations against topoisomerase IV as measured in a decatenation activity assay and against DNA gyrase as measured in a supercoiling activity assay. Good antibacterial activities (< or =1 microg/ml) against staphylococcal gyrA grlA double mutants, as well as low frequencies (10(-9) to 10(-10)) of selection of still higher-level mutants, also suggested that HITZs remained active against mutant enzymes. We further demonstrated that HITZs exhibit good inhibition of both S. aureus mutant enzymes and thus continue to possess a novel dual-targeting mode of action against these mutant strains. In stepwise acquisition of mutations, HITZs selected quinolone resistance determining region mutations gyrA(Ser84Leu), grlA(Ser80Phe), grlA(Ala116Val), and gyrA(Glu88Lys) sequentially, suggesting that the corresponding amino acids are key amino acids involved in the binding of HITZs to topoisomerases. The overall profile of these compounds suggests the potential utility of HITZs in combating infections caused by S. aureus, including multidrug-resistant MRSA.
Authors:
Jijun Cheng; Jane A Thanassi; Christy L Thoma; Barton J Bradbury; Milind Deshpande; Michael J Pucci
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Publication Detail:
Type:  Comparative Study; Journal Article     Date:  2007-05-14
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  51     ISSN:  0066-4804     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-08-08     Completed Date:  2007-10-30     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2445-53     Citation Subset:  IM    
Affiliation:
Achillion Pharmaceuticals, New Haven, CT 06511, USA.
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MeSH Terms
Descriptor/Qualifier:
Anti-Bacterial Agents / chemistry,  pharmacology*
DNA Gyrase / antagonists & inhibitors*,  genetics
DNA Topoisomerase IV / antagonists & inhibitors*
Drug Resistance, Bacterial / drug effects,  genetics
Enzyme Inhibitors / chemistry,  pharmacology*
Humans
Inhibitory Concentration 50
Microbial Sensitivity Tests
Molecular Structure
Mutation
Quinolones / pharmacology
Staphylococcus aureus / drug effects*,  enzymology,  genetics,  isolation & purification
Thiazoles / pharmacology
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Enzyme Inhibitors; 0/Quinolones; 0/Thiazoles; EC 5.99.1.-/DNA Gyrase; EC 5.99.1.-/DNA Topoisomerase IV
Comments/Corrections

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