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

  • J Med Chem. 2018 Sep 27;61(18):8337-8352. doi: 10.1021/acs.jmedchem.8b00832.
Clare F Vickers  1 ,  Ana P G Silva  2 ,  Ajanta Chakraborty  2 ,  Paulina Fernandez  2 ,  Natalia Kurepina  3 ,  Charis Saville  2 ,  Yandi Naranjo  4 ,  Miquel Pons  4 ,  Laura S Schnettger  5 ,  Maximiliano G Gutierrez  5 ,  Steven Park  3 ,  Barry N Kreiswith  3 ,  David S Perlin  3 ,  Eric J Thomas  1 ,  Jennifer S Cavet  2 ,  Lydia Tabernero  2
Affiliations
  • 1. The School of Chemistry , University of Manchester , Manchester M13 9PL , United Kingdom.
  • 2. School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre , University of Manchester , Manchester M13 9PT , United Kingdom.
  • 3. Public Health Research Institute , New Jersey Medical School, Rutgers University , 225 Warren Street , Newark , New Jersey 07103 , United States.
  • 4. Departament de Química Inorgànica i Orgànica , Universitat de Barcelona , Baldiri Reixac, 10-12 , 08028 Barcelona , Spain.
  • 5. Host-Pathogen Interactions in Tuberculosis Laboratory , The Francis Crick Institute , 1 Midland Road , NW1 1AT London , United Kingdom.
PMID: 30153005 DOI: 10.1021/acs.jmedchem.8b00832
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.

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