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

Sae Woong Park, Dominick E. Casalena, Daniel J. Wilson, Ran Dai, Partha P. Nag, Feng Liu, Jim P. Boyce, Joshua A. Bittker, Stuart L. Schreiber, Barry C. Finzel, Dirk Schnappinger, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)76-86
Number of pages11
JournalChemistry and Biology
Issue number1
StatePublished - Jan 22 2015

Bibliographical note

Funding Information:
This work was funded in part by grants from the NIH (R03 MH096537 to C.C.A. and R01AI091790 to D.S.) and by the NIH-MLPCN program (1 U54 HG005032-1 awarded to S.L.S.). We also gratefully acknowledge support from the University of Minnesota Bighley Graduate Fellowship (to R.D.) and resources from the University of Minnesota Supercomputing Institute.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

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