Work

Discovery of novel bacterial topoisomerase I inhibitors by use of in silico docking and in vitro assays

Year: 2018

Type: article

Abstract: Topoisomerases are important targets for antibacterial and anticancer therapies. Bacterial topoisomerase I remains to be exploited for antibiotics that can be used in the clinic. Inhibitors of bacterial topoisomerase I may provide leads for novel antibacterial drugs against pathogens resistant to current antibiotics. TB is the leading infectious cause of death worldwide, and new TB drugs against an alternative target are urgently needed to overcome multi-drug resistance.Mycobacterium tuberculosistopoisomerase I (MtbTopI) has been validated genetically and chemically as a TB drug target. Here we conductedin silicoscreening targeting an active site pocket of MtbTopI. The top hits were assayed for inhibition of MtbTopI activity. The shared structural motif found in the active hits was utilized in a second round ofin silicoscreening andin vitroassays, yielding selective inhibitors of MtbTopI with IC50s as low as 2 µM. Growth inhibition ofMycobacterium smegmatisby these compounds in combination with an efflux pump inhibitor was diminished by the overexpression of recombinant MtbTopI. This work demonstrates thatin silicoscreening can be utilized to discover new bacterial topoisomerase I inhibitors, and identifies a novel structural motif which could be explored further for finding selective bacterial topoisomerase I inhibitors.

Source: Scientific Reports

DOI: 10.1038/s41598-018-19944-4

Authors: Shayna Sandhaus, Prem P. Chapagain, Yuk-Ching Tse-Dinh

Institution: Florida International University

Language: English

Topic: Computational Drug Discovery Methods

Subfield: Computational Theory and Mathematics

Field: Computer Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,690