Abstract
Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / chemistry*
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Antitubercular Agents / chemistry
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Antitubercular Agents / therapeutic use*
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Chemistry, Pharmaceutical / methods
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Crystallography, X-Ray / methods
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Drug Design
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Drug Resistance, Multiple
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Fluoroquinolones / pharmacology
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Gatifloxacin
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Humans
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Inhibitory Concentration 50
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Microbial Sensitivity Tests
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Models, Chemical
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Molecular Conformation
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Mycobacterium bovis / metabolism
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / metabolism
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Tuberculosis / drug therapy*
Substances
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Antitubercular Agents
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Fluoroquinolones
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Amidohydrolases
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peptide deformylase
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Gatifloxacin