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

Vickers, CF; Silva, APG; Chakraborty, A; Fernandez, P; Kurepina, N; Saville, C; Naranjo, Y; Pons, M; Schnettger, LS; Gutierrez, MG; Park, S; Kreiswith, BN; Perlin, DS; Thomas, EJ; Cavet, JS; Tabernero, L

JOURNAL OF MEDICINAL CHEMISTRY
2018
VL / 61 - BP / 8337 - EP / 8352
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.

AccesS level

Green Accepted, Green Published, Other Gold

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PROYECTO FINANCIADO POR PLAN NACIONAL DE INVESTIGACIÓN AGENCIA ESTATAL DE INVESTIGACIÓN, MINISTERIO DE CIENCIA E INNOVACIÓN. PID2019-109127RB-I00