Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo.
Clare F VickersAna P G SilvaAjanta ChakrabortyPaulina FernandezNatalia KurepinaCharis SavilleYandi NaranjoMiquel PonsLaura S SchnettgerMaximiliano G GutierrezSteven ParkBarry N KreiswithDavid S PerlinEric J ThomasJennifer S CavetLydia TaberneroPublished in: Journal of medicinal chemistry (2018)
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.
Keyphrases
- mycobacterium tuberculosis
- multidrug resistant
- pulmonary tuberculosis
- drug resistant
- gram negative
- escherichia coli
- acinetobacter baumannii
- klebsiella pneumoniae
- liver failure
- pseudomonas aeruginosa
- free survival
- staphylococcus aureus
- risk factors
- respiratory failure
- antimicrobial resistance
- biofilm formation
- amino acid
- aortic dissection
- extracorporeal membrane oxygenation
- study protocol
- human immunodeficiency virus
- hiv aids
- protein kinase