Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase

Aldred, K.J.; Blower, T.R.; Kerns, R.J.; Berger, J.M.; Osheroff, N.

Abstract

Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrAA90 and GyrAD94. M. tuberculosis gyrase lacks a conserved serine that anchors a water–metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrAA90) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone–gyrase interactions. Clinically relevant mutations at GyrAA90 and GyrAD94 cause quinolone resistance by disrupting the bridge–enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone–enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrAA90V and GyrAD94G. 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug–enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis.

Citation

Aldred, K., Blower, T., Kerns, R., Berger, J., & Osheroff, N. (2016). Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase. Proceedings of the National Academy of Sciences, 113(7), E839-E846. https://doi.org/10.1073/pnas.1525055113

• Journal Article Type: Article
• Acceptance Date: Dec 21, 2015
• Online Publication Date: Jan 20, 2016
• Publication Date: Feb 16, 2016
• Deposit Date: Jan 21, 2016
• Publicly Available Date: Sep 16, 2016
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 113
• Issue: 7
• Pages: E839-E846
• DOI: https://doi.org/10.1073/pnas.1525055113
• Keywords: Mycobacterium tuberculosis, Fluoroquinolones, Antibiotic resistance, Gyrase, Complex stability.
• Public URL: https://durham-repository.worktribe.com/output/1391063