Small-Molecule Inhibitors Targeting Topoisomerase I As Novel Antituberculosis Agents

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.

Publication Date

7-1-2016

Publication Title

Antimicrobial Agents and Chemotherapy

Volume

60

Issue

7

Number of Pages

4028-4036

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1128/AAC.00288-16

Socpus ID

84977151043 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84977151043

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