Journal article
Bypassing Fluoroquinolone Resistance with Quinazolinediones: Studies of Drug-Gyrase-DNA Complexes Having Implications for Drug Design
ACS chemical biology, Vol.9(12), pp.2895-2904
12/01/2014
DOI: 10.1021/cb500629k
PMCID: PMC4273985
PMID: 25310082
Abstract
Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drugtopoisomeraseDNA complexes in which the DNA moiety is broken) with gyrase, one of two bacterial targets of the drugs. Formation of cleaved complexes, measured by linearization of a circular DNA substrate, required lower concentrations of quinolone than dione. The reverse reaction, detected as resealing of DNA breaks in cleaved complexes, required higher temperatures and EDTA concentrations for quinolones than diones. The greater stability of quinolone-containing complexes was attributed to the unique ability of the quinolone C3/C4 keto acid to complex with magnesium and form a previously described drugmagnesiumwater bridge with GyrA-Ser83 and GyrA-Asp87. A nearby substitution in GyrA (G81C) reduced activity differences between quinolone and dione, indicating that resistance due to this variation derives from perturbation of the magnesiumwater bridge. To increase dione activity, we examined a relatively small, flexible C-7-3-(aminomethyl)pyrrolidinyl substituent, which is distal to the bridging C3/C4 keto acid substituent of quinolones. The 3-(aminomethyl)pyrrolidinyl group at position C-7 was capable of forming binding interactions with GyrB-Glu466, as indicated by inspection of crystal structures, computer-aided docking, and measurement of cleaved-complex formation with mutant and wild-type GyrB proteins. Thus, modification of dione C-7 substituents constitutes a strategy for obtaining compounds active against common quinolone-resistant mutants.
Details
- Title: Subtitle
- Bypassing Fluoroquinolone Resistance with Quinazolinediones: Studies of Drug-Gyrase-DNA Complexes Having Implications for Drug Design
- Creators
- Karl Drlica - Rutgers, The State University of New JerseyArkady Mustaev - Rutgers, The State University of New JerseyTyrell R. Towle - University of IowaGan Luan - Rutgers Biomedical and Health SciencesRobert J. Kerns - Univ Iowa, Div Med & Nat Prod Chem, Dept Pharmaceut Sci & Expt Therapeut, Coll Pharm, Iowa City, IA 52246 USAJames M. Berger - University of California, Berkeley
- Resource Type
- Journal article
- Publication Details
- ACS chemical biology, Vol.9(12), pp.2895-2904
- DOI
- 10.1021/cb500629k
- PMID
- 25310082
- PMCID
- PMC4273985
- NLM abbreviation
- ACS Chem Biol
- ISSN
- 1554-8929
- eISSN
- 1554-8937
- Publisher
- Amer Chemical Soc
- Number of pages
- 10
- Grant note
- R01AI073491 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T32GM067795 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01AI073491; R01AI87671; R01CA077373 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA077373 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 12/01/2014
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365882502771
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