Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.

Autor:	Mann CA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio, USA., Carvajal Moreno JJ; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio, USA., Lu Y; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio, USA., Dellos-Nolan S; Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University , Columbus, Ohio, USA., Wozniak DJ; Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University , Columbus, Ohio, USA., Yalowich JC; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio, USA., Mitton-Fry MJ; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2023 Oct 18; Vol. 67 (10), pp. e0048223. Date of Electronic Publication: 2023 Sep 19.
DOI:	10.1128/aac.00482-23
Abstrakt:	Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique binding mode and distinct pharmacology that enables them to evade existing resistance mechanisms. The clinical development of NBTIs has been plagued by several issues, including cardiovascular safety. Herein, we report a sub-series of tricyclic NBTIs bearing an amide linkage that displays promising antibacterial activity, potent dual-target inhibition of DNA gyrase and topoisomerase IV (TopoIV), as well as improved cardiovascular safety and metabolic profiles. These amide NBTIs induced both single- and double-strand breaks in pBR322 DNA mediated by Staphylococcus aureus DNA gyrase, in contrast to prototypical NBTIs that cause only single-strand breaks. Unexpectedly, amides 1a and 1b targeted human topoisomerase IIα (TOP2α) causing both single- and double-strand breaks in pBR322 DNA, and induced DNA strand breaks in intact human leukemia K562 cells. In addition, anticancer drug-resistant K/VP.5 cells containing decreased levels of TOP2α were cross-resistant to amides 1a and 1b . Together, these results demonstrate broad spectrum antibacterial properties of selected tricyclic NBTIs, desirable safety profiles, an unusual ability to induce DNA double-stranded breaks, and activity against human TOP2α. Future work will be directed toward optimization and development of tricyclic NBTIs with potent and selective activity against bacteria. Finally, the current results may provide an additional avenue for development of selective anticancer agents. Competing Interests: M.J.M.-F. is a shareholder of Pfizer.
Databáze:	MEDLINE
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