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

TitleStructure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsLiu F, Dawadi S, Maize KM, Dai R, Park SWoong, Schnappinger D, Finzel BC, Aldrich CC
JournalJ Med Chem
Volume60
Issue13
Pagination5507-5520
Date Published2017 07 13
ISSN1520-4804
KeywordsAnti-Bacterial Agents, Bacterial Proteins, Biocatalysis, Biotin, Dose-Response Relationship, Drug, Microbial Sensitivity Tests, Molecular Structure, Mycobacterium tuberculosis, Piperazines, Pyridoxal Phosphate, Structure-Activity Relationship, Transaminases
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 K of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.

DOI10.1021/acs.jmedchem.7b00189
Alternate JournalJ Med Chem
PubMed ID28594172
PubMed Central IDPMC5590679
Grant ListR01 AI091790 / AI / NIAID NIH HHS / United States
S10 OD017982 / OD / NIH HHS / United States

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