Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents.
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.
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
Shayna
S
Sandhaus
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
Thirunavukkarasu
T
Annamalai
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA.
Greg
G
Welmaker
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA.
Richard A
RA
Houghten
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
Carlos
C
Paz
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
Pamela K
PK
Garcia
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
Angelo
A
Andres
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
Gagandeep
G
Narula
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Carolina
C
Rodrigues Felix
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Sandra
S
Geden
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Mandy
M
Netherton
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Rashmi
R
Gupta
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Kyle H
KH
Rohde
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA.
Marc A
MA
Giulianotti
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA Biomolecular Sciences Institute, Florida International University, Miami, Florida, USA yukching.tsedinh@fiu.edu.
Yuk-Ching
YC
Tse-Dinh
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000235:genetics / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D059004:Topoisomerase I Inhibitors; D027101:DNA Topoisomerase IV; D004264:DNA Topoisomerases, Type I; D027081:DNA Gyrase