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

18 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

Bibliographical note

Funding Information:
This research also used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The authors also acknowledge the use of beamline 4.2.2 (Molecular Biology Consortium) at the Advanced Light Source and thank the beamline director, Jay Nix. This research used resources of the Advanced Light Source, which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231.

Publisher Copyright:
© 2017 American Chemical Society.

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