2. Academic Validation
  3. Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo

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

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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