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

Clare F. Vickers, Ana P.G. 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

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8337-8352
Number of pages16
JournalJournal of medicinal chemistry
Volume61
Issue number18
DOIs
StatePublished - Sep 27 2018

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Molecular Medicine

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    Vickers, C. F., Silva, A. P. G., Chakraborty, A., Fernandez, P., Kurepina, N., Saville, C., Naranjo, Y., Pons, M., Schnettger, L. S., Gutierrez, M. G., Park, S., Kreiswith, B. N., Perlin, D. S., Thomas, E. J., Cavet, J. S., & Tabernero, L. (2018). Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo. Journal of medicinal chemistry, 61(18), 8337-8352. https://doi.org/10.1021/acs.jmedchem.8b00832