The development of small molecule inhibitors of mycobacterium protein tyrosine phosphatase B for the treatment of mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of Tuberculosis (TB) is estimated to cause nearly two million deaths worldwide each year. Current therapy for patients with drug-sensitive TB involves dosing with a combination of antibiotics over 6 months. The likelihood of recovery is high but drops to 54% for cases of multidrug resistant TB (MDRTB) and 30% for patients suffering from extremely drug resistant TB (XDR-TB) with complications exacerbated by a high rate of relapse. New therapeutics targeting TB via novel pathways are required. The focus of this project was to develop a small molecule for the treatment of tuberculosis by targeting mycobacterium protein tyrosine phosphatase B (MptpB), a virulence factor secreted into the cytoplasm of macrophages which facilitates bacterial survival by disrupting host signalling cascades. During the course of this project four active chemical series were developed: the triazole series, imidazole series, pyridine series and dioxoisothiazolone series. Of these, the triazole series research was most successful culminating in 142, a molecule with a biochemical activity of 2.5 nM, high kinetic solubility and cellular permeability. Eight compounds, including 142, were tested for antimicrobial activity in murine bone marrow derived macrophages (BMDMs) infected with m. bovis. Compounds were tested alone and in combination with Rifampicin and Isoniazid with lead compounds shown to potentiate the effect of the antibiotic by 0.5 log units.