Abstract
BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 Å resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antitubercular Agents / chemical synthesis
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism*
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Biocatalysis
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Biotin / biosynthesis*
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Structure
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Mycobacterium tuberculosis / drug effects
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Mycobacterium tuberculosis / enzymology*
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Pyridones / chemical synthesis
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Pyridones / chemistry
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Pyridones / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Transaminases / antagonists & inhibitors
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Transaminases / chemistry
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Transaminases / metabolism*
Substances
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Antitubercular Agents
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Bacterial Proteins
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Pyridones
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Biotin
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Transaminases
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BioA protein, bacteria