Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis.

Chem Biol
Authors
Keywords
Abstract

Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts.

Year of Publication
2015
Journal
Chem Biol
Volume
22
Issue
1
Pages
76-86
Date Published
2015 Jan 22
ISSN
1879-1301
DOI
10.1016/j.chembiol.2014.11.012
PubMed ID
25556942
PubMed Central ID
PMC4305006
Links
Grant list
R03 MH096537 / MH / NIMH NIH HHS / United States
R01AI091790 / AI / NIAID NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
1 U54 HG005032-1 / HG / NHGRI NIH HHS / United States
R01 AI091790 / AI / NIAID NIH HHS / United States