Abstract
Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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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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Drug Design*
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Drug Resistance, Multiple / drug effects
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Female
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Guinea Pigs
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Macrophages / drug effects*
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Macrophages / microbiology
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Macrophages / pathology
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Male
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Models, Molecular
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Molecular Structure
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Mycobacterium tuberculosis / drug effects*
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Protein Conformation
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / chemistry
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Structure-Activity Relationship
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Tuberculosis, Multidrug-Resistant / drug therapy*
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Tuberculosis, Multidrug-Resistant / microbiology
Substances
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Antitubercular Agents
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Bacterial Proteins
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MptpA protein, Mycobacterium tuberculosis
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Protein Tyrosine Phosphatases