Structure-Based Optimization of Pyridoxal 5′-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis

Feng Liu, Surendra Dawadi, Kimberly M. Maize, Ran Dai, Sae Woong Park, Dirk Schnappinger, Barry C. Finzel, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.

Original languageEnglish (US)
Pages (from-to)5507-5520
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number13
DOIs
StatePublished - Jul 13 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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