Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914.

Abstract

We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467-474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β.

• Authors: Gunther Kern, Tiffany Palmer, David E Ehmann, Adam B Shapiro, Beth Andrews, Gregory S Basarab, Peter Doig, Jun Fan, Ning Gao, Scott D Mills, John Mueller, Shubha Sriram, Jason Thresher, Grant K Walkup
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 34 Pg. 20984-20994 (Aug 21 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26149691 (Publication Type: Journal Article)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Anti-Bacterial Agents
• Barbiturates
• DNA, Bacterial
• Fluoroquinolones
• Isoxazoles
• Morpholines
• Oxazolidinones
• Spiro Compounds
• Topoisomerase II Inhibitors
• Ciprofloxacin
• DNA
• DNA Topoisomerase IV
• DNA Gyrase
• zoliflodacin

Topics

• Anti-Bacterial Agents (pharmacology)
• Barbiturates (pharmacology)
• Ciprofloxacin (pharmacology)
• Clinical Trials as Topic
• DNA (chemistry, metabolism)
• DNA Gyrase (genetics, metabolism)
• DNA Topoisomerase IV (antagonists & inhibitors, genetics, metabolism)
• DNA, Bacterial (chemistry, metabolism)
• Drug Resistance, Bacterial (drug effects)
• Escherichia coli (drug effects, enzymology, genetics)
• Fluoroquinolones (pharmacology)
• Gene Expression
• Humans
• Isoxazoles
• Morpholines
• Mutation
• Neisseria gonorrhoeae (drug effects, enzymology, genetics)
• Oxazolidinones
• Species Specificity
• Spiro Compounds (pharmacology)
• Topoisomerase II Inhibitors (pharmacology)