Identification of Pks13 Inhibitors for Antitubercular Drug Discovery

Abstract

Frontline tuberculosis drugs, i.e. Isoniazid, have become inefficient as strains of Mycobacterium Tuberculosis have become multi-drug resistant, creating an urgent need for novel antitubercular drugs. The key to the bacterium resistance lies within its thick and complex cell wall, where mycolic acids (MAs) are the major constituents and contribute to the permeability of the cell wall and the resistance of the organism. The last step in their biosynthetic formation is done by polyketide synthase 13, which produces the α-alkyl-β-ketoester precursors leading to MAs formation. We have identified a compound in previous studies, IMTB-28, able to bind to the Pks13 Thioesterase domain, a domain where no major research has been done before. Inhibition of Pks13 TE domain by IMTB-28 prompt structural changes in Pks13 that make it unable to function properly and stop product formation. This research identified a compound, TAMU196, within a series of IMTB-28 analogs, with great potency against the Pks13 TE domain and Mtb cells, and low toxicity against human cells. Eight commercially available compounds were also identified having 100% inhibition against the Pks13 TE domain at 10 μM concentration. These inhibitors can be used as scaffolds for structural changes in the path to becoming the next antitubercular drug and save the lives of patients with multi-drug resistant tuberculosis worldwide.