Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents.

Autor:	Sandhaus S; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA., Annamalai T; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA., Welmaker G; Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA., Houghten RA; Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA., Paz C; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA., Garcia PK; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA., Andres A; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA., Narula G; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA., Rodrigues Felix C; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA., Geden S; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA., Netherton M; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA., Gupta R; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA., Rohde KH; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA., Giulianotti MA; Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA., Tse-Dinh YC; Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA Biomolecular Sciences Institute, Florida International University, Miami, Florida, USA yukching.tsedinh@fiu.edu.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2016 Jun 20; Vol. 60 (7), pp. 4028-36. Date of Electronic Publication: 2016 Jun 20 (Print Publication: 2016).
DOI:	10.1128/AAC.00288-16
Abstrakt:	Bacterial topoisomerase functions are required for regulation of DNA supercoiling and overcoming the DNA topological barriers that are encountered during many vital cellular processes. DNA gyrase and topoisomerase IV of the type IIA bacterial topoisomerase family are important clinical targets for antibacterial therapy. Topoisomerase I, belonging to the type IA topoisomerase family, has recently been validated as a potential antitubercular target. The topoisomerase I activity has been shown to be essential for bacterial viability and infection in a murine model of tuberculosis. Mixture-based combinatorial libraries were screened in this study to identify novel bacterial topoisomerase I inhibitors. Using positional-scanning deconvolution, selective small-molecule inhibitors of bacterial topoisomerase I were identified starting from a polyamine scaffold. Antibacterial assays demonstrated that four of these small-molecule inhibitors of bacterial topoisomerase I are bactericidal against Mycobacterium smegmatis and Mycobacterium tuberculosis The MICs for growth inhibition of M. smegmatis increased with overexpression of recombinant M. tuberculosis topoisomerase I, consistent with inhibition of intracellular topoisomerase I activity being involved in the antimycobacterial mode of action. (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
Databáze:	MEDLINE
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