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

[Image: see text] 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 strain...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Eric J., Cavet, Jennifer S., Tabernero, Lydia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459586/
https://www.ncbi.nlm.nih.gov/pubmed/30153005
http://dx.doi.org/10.1021/acs.jmedchem.8b00832
Descripción
Sumario:[Image: see text] 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.

Ejemplares similares