Polyketide synthase 13 (Pks13)

Polyketide synthase 13 (Pks13) is a vital multifunctional enzyme in Mycobacterium tuberculosis that plays a critical role in the final stages of mycolic acid biosynthesis. It facilitates the Claisen-type condensation of two fatty acid chains—a long meromycolate chain and a shorter alpha-chain—to produce alpha-alkyl beta-ketoesters, which are the immediate precursors of mycolic acids. These acids are essential components of the mycobacterial cell wall, providing structural integrity and resistance to both host immune defenses and antibiotic penetration. Because Pks13 is essential for bacterial viability and has no human ortholog, it is a highly attractive target for the development of new antitubercular agents, particularly for treating multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains. Several chemical scaffolds have been identified as Pks13 inhibitors, including benzofurans like TAM16, thiophenes, and coumestans, which typically target the enzyme's thioesterase (TE) or acyl carrier protein (ACP) domains. Inhibition of Pks13 results in the depletion of mycolic acids, leading to rapid cell wall breakdown and bacterial death. Despite its therapeutic promise, drug development efforts must address potential challenges such as hERG-related cardiotoxicity and the emergence of resistance through point mutations in the pks13 gene.

Other names

pks13 gene productPolyketide synthase Pks13Mycolic acid condensasePKS13_MYCTU

Inhibition of the final condensation step in mycolic acid biosynthesis by blocking the activity of the Pks13 enzyme, often through binding to the thioesterase (TE) or acyl carrier protein (ACP) domains, thereby preventing the formation of essential cell wall precursors.