Polyketide synthase 13 (Pks13) is responsible for synthesizing the mycobacteria cell wall component mycolic acids. This multidomain enzyme is categorized into a unique group of non-modular, non-iterative polyketide synthases. Unlike other PKSs, which catalyze cycles of chain elongation using short-chain (typically C2 to C4) α-carboxylated acyl-CoAs as building blocks, Pks13’s sole activity is to condense C26 and ~C60 lipids to form a ~C90 ultra-long-chain mycolic acid lipid.
Pks13 consists of five domains, among which the ketosynthase, acyltransferase, and thioesterase domains bear enzymatic activities. We have identified inhibitors targeting each of the three domains. Since Pks13 is a novel anti-TB target, these inhibitors do not show cross-resistance with the classical anti-TB drugs.