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

Journal of Medicinal Chemistry
Clare F VickersLydia Tabernero

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.

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Citations

Mar 5, 2019·Current Topics in Medicinal Chemistry·Matteo MoriLaurent Roberto Chiarelli
Mar 28, 2019·FEMS Microbiology Reviews·Claudio Bussi, Maximiliano G Gutierrez
Dec 31, 2020·Microorganisms·Kasi Viswanatharaju RuddrarajuZhong-Yin Zhang
Apr 3, 2021·Frontiers in Cellular and Infection Microbiology·Hee-Jeong YangLaura E Via
May 30, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Nelson G M GomesPaula B Andrade
Aug 26, 2021·Biochemical Society Transactions·Aaron D Krabill, Zhong-Yin Zhang
Apr 8, 2020·Journal of Medicinal Chemistry·Vadim MakarovSean Ekins

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Methods Mentioned

BETA
column chromatography
NMR
PMA
transfection

Software Mentioned

Graphpad Prism
Autodock4
PyMol

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