The Francis Crick Institute
acs.jmedchem.8b00832.pdf (4.31 MB)

Structure-based design of MptpB inhibitors that reduce multidrug-resistant Mycobacterium tuberculosis survival and infection burden in vivo

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journal contribution
posted on 2020-09-14, 10:48 authored by Clare F Vickers, Ana PG Silva, Ajanta Chakraborty, Paulina Fernandez, Natalia Kurepina, Charis Saville, Yandi Naranjo, Miquel Pons, Laura S Schnettger, Maximiliano G Gutierrez, Steven Park, Barry N Kreiswith, David S Perlin, Eric J Thomas, Jennifer S Cavet, Lydia Tabernero
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.