Structure-based design of MptpB inhibitors that reduce multidrug-resistant Mycobacterium tuberculosis survival and infection burden in vivo
journal contributionposted on 14.09.2020, 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.
AnimalsAntitubercular AgentsBacterial ProteinsDrug DesignDrug Resistance, MultipleFemaleGuinea PigsMacrophagesMaleModels, MolecularMolecular StructureMycobacterium tuberculosisProtein ConformationProtein Tyrosine PhosphatasesStructure-Activity RelationshipTuberculosis, Multidrug-ResistantGutierrez FC001092Medicinal & Biomolecular Chemistry0304 Medicinal and Biomolecular Chemistry1115 Pharmacology and Pharmaceutical Sciences0305 Organic Chemistry