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

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.

SUBMITTER: Vickers CF

PROVIDER: S-EPMC6459586 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Vickers Clare F CF Silva Ana P G APG Chakraborty Ajanta A Fernandez Paulina P Kurepina Natalia N Saville Charis C Naranjo Yandi Y Pons Miquel M Schnettger Laura S LS Gutierrez Maximiliano G MG Park Steven S Kreiswith Barry N BN Perlin David S DS Thomas Eric J EJ Cavet Jennifer S JS Tabernero Lydia L

Journal of medicinal chemistry 20180910 18

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 ...[more]

PMID: 30153005

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