Actions of a Novel Bacterial Topoisomerase Inhibitor against Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks

Author:

Dauda Soziema E.1,Collins Jessica A.1ORCID,Byl Jo Ann W.1,Lu Yanran2,Yalowich Jack C.3ORCID,Mitton-Fry Mark J.2,Osheroff Neil145ORCID

Affiliation:

1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

2. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA

3. Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 42310, USA

4. Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232, USA

5. VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA

Abstract

Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by Neisseria gonorrhoeae gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by N. gonorrhoeae gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant N. gonorrhoeae topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.

Funder

US Veterans Administration Merit Review Award

Dr. Ralph and Marian Fak Medical Research Trust

National Institutes of Health

Aspirnaut Undergraduate Discovery Science Experience in Renal Biology and Disease

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference68 articles.

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2. Fisher, J.F., Mobashery, S., and Miller, M.J. (2018). Antibacterials: Volume I, Springer International Publishing.

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4. Mechanism of quinolone action and resistance;Aldred;Biochemistry,2014

5. Mechanisms of drug resistance: Quinolone resistance;Hooper;Ann. N. Y. Acad. Sci.,2015

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