Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents

Authors

Shayna Sandhaus, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Thirunavukkarasu Annamalai, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Greg Welmaker, Torrey Pines Institute for Molecular Studies
Richard A. Houghten, Torrey Pines Institute for Molecular Studies
Carlos Paz, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Pamela K. Garcia, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Angelo Andres, Department of Chemistry and Biochemistry, Florida International University
Gagandeep Narula, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Carolina Rodrigues Felix, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida
Sandra Geden, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida
Mandy Netherton, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida
Rashmi Gupta, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida
Kyle H. Rohde, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida
Marc A. Giulianotti, Torrey Pines Institute for Molecular Studies
Yuk-Ching Tse-Dinh, Department of Chemistry and Biochemistry and Biomolecular Sciences Institute, Florida International UniversityFollow

Date of this Version

7-1-2016

Document Type

Article

Rights

default

Abstract

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.

DOI

10.1128/AAC.00288-16

Identifier

27114277

Comments

n Sandhaus S, Annamalai T, Welmaker G, Houghten RA, Paz C, Garcia PK, Andres A, Narula G, Rodrigues Felix C, Geden S, Netherton M, Gupta R, Rohde KH, Giulianotti MA, Tse-Dinh Y-C. 2016. Small-molecule inhibitors targeting topoisomerase I as novel antituberculosis agents. Antimicrob Agents Chemother 60:4028 –4036. doi:10.1128/AAC.00288-16.

Recommended Citation

Sandhaus, Shayna; Annamalai, Thirunavukkarasu; Welmaker, Greg; Houghten, Richard A.; Paz, Carlos; Garcia, Pamela K.; Andres, Angelo; Narula, Gagandeep; Rodrigues Felix, Carolina; Geden, Sandra; Netherton, Mandy; Gupta, Rashmi; Rohde, Kyle H.; Giulianotti, Marc A.; and Tse-Dinh, Yuk-Ching, "Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents" (2016). Biomolecular Sciences Institute: Faculty Publications. 67.
https://digitalcommons.fiu.edu/biomolecular_fac/67