Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
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, Er
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.
Green published, Green accepted, Hybrid
Among papers in Pharmacology & Toxicology