Logo image
Back
Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions
Journal article   Open access   Peer reviewed

Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions

Katie J Aldred, Heidi A Schwanz, Gangqin Li, Sylvia A McPherson, Charles L Turnbough Jr, Robert J Kerns and Neil Osheroff
ACS chemical biology, Vol.8(12), pp.2660-2668
12/20/2013
DOI: 10.1021/cb400592n
PMCID: PMC3870039
PMID: 24047414
url
https://www.ncbi.nlm.nih.gov/pmc/articles/3870039View
Open Access

Abstract

Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.
 Mutation Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antigens, Neoplasm - chemistry Antigens, Neoplasm - genetics Antigens, Neoplasm - metabolism Bacillus anthracis - chemistry Bacillus anthracis - drug effects Bacillus anthracis - enzymology Bacillus anthracis - genetics Cations, Divalent DNA Cleavage - drug effects DNA Topoisomerase IV - antagonists & inhibitors DNA Topoisomerase IV - chemistry DNA Topoisomerase IV - genetics DNA Topoisomerase IV - metabolism DNA Topoisomerases, Type II - chemistry DNA Topoisomerases, Type II - genetics DNA Topoisomerases, Type II - metabolism DNA, Bacterial - chemistry DNA, Bacterial - metabolism DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Resistance, Bacterial - drug effects Humans Kinetics Magnesium - chemistry Magnesium - metabolism Quinazolinones - chemistry Quinazolinones - pharmacology Quinolones - chemistry Quinolones - pharmacology Recombinant Proteins - chemistry Recombinant Proteins - genetics Recombinant Proteins - metabolism Species Specificity Structure-Activity Relationship Water - chemistry

Details

Metrics

14 Record Views
58 Times Cited - Web of Science
Logo image