Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo

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 a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-09, Vol.61 (18), p.8337-8352
Main Authors: Vickers, Clare F, Silva, Ana P. G, Chakraborty, Ajanta, Fernandez, Paulina, Kurepina, Natalia, Saville, Charis, Naranjo, Yandi, Pons, Miquel, Schnettger, Laura S, Gutierrez, Maximiliano G, Park, Steven, Kreiswith, Barry N, Perlin, David S, Thomas, Eric J, Cavet, Jennifer S, Tabernero, Lydia
Format: Article
Language:English
Subjects:
Animals
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Drug Design
Drug Resistance, Multiple - drug effects
Female
Guinea Pigs
Macrophages - drug effects
Macrophages - microbiology
Macrophages - pathology
Male
Models, Molecular
Molecular Structure
Mycobacterium tuberculosis - drug effects
Protein Conformation
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - chemistry
Structure-Activity Relationship
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - microbiology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00832