Discovery of <i>Mycobacterium tuberculosis</i> Protein Tyrosine Phosphatase B (PtpB) Inhibitors from Natural Products

<div><p>Protein tyrosine phosphatase B (PtpB) is one of the virulence factors secreted into the host cell by <i>Mycobacterium tuberculosis</i>. PtpB attenuates host immune defenses by interfering with signal transduction pathways in macrophages and, therefore, it is considered a promising target for the development of novel anti-tuberculosis drugs. Here we report the discovery of natural compound inhibitors of PtpB among an <i>in house</i> library of more than 800 natural substances by means of a multidisciplinary approach, mixing <i>in silico</i> screening with enzymatic and kinetics studies and MS assays. Six natural compounds proved to inhibit PtpB at low micromolar concentrations (< 30 µM) with Kuwanol E being the most potent with <i>K</i>_i = 1.6 ± 0.1 µM. To the best of our knowledge, Kuwanol E is the most potent natural compound PtpB inhibitor reported so far, as well as it is the first non-peptidic PtpB inhibitor discovered from natural sources. Compounds herein identified may inspire the design of novel specific PtpB inhibitors.</p>