Mycobacterium tuberculosis mycolic acid biosynthesis pathway

The Mycobacterium tuberculosis mycolic acid biosynthesis pathway is a critical metabolic route responsible for the production of long-chain fatty acids (C60-C90) that are essential components of the mycobacterial cell wall (Marrakchi et al., 2014). These mycolic acids provide a thick, waxy permeability barrier that protects the bacterium from host immune responses and limits the entry of many antibiotics (Takayama et al., 2005). The pathway involves two distinct systems: Fatty Acid Synthase I (FAS-I), which generates short-chain fatty acid precursors, and Fatty Acid Synthase II (FAS-II), which extends these precursors into mature mycolic acids through a series of elongation and modification steps (Nataraj et al., 2015). Key enzymes in this pathway, such as the enoyl-ACP reductase (InhA) and beta-ketoacyl-ACP synthases (KasA/B), are the primary targets for several essential anti-tuberculosis drugs, including isoniazid and ethionamide (Vilchèze & Jacobs, 2007). Inhibition of these enzymes disrupts cell wall assembly, leading to bacterial cell death and making this pathway one of the most successful targets in the history of tuberculosis chemotherapy (North et al., 2014). Because the enzymes involved in mycolic acid synthesis are unique to mycobacteria and lack human homologs, they offer high selectivity for drug development, although the rise of multi-drug resistant strains necessitates the discovery of new inhibitors within the pathway (WHO, 2023).

Other names

Mycolic acid synthesis pathwayFAS-I/FAS-II systemMycobacterial cell wall biosynthesisMycolic acid biosynthetic process

The pathway is targeted through the inhibition of essential enzymes involved in the synthesis and assembly of mycolic acids. Isoniazid and ethionamide are prodrugs that, upon activation, form adducts with NAD(H) to inhibit the enoyl-ACP reductase InhA, thereby blocking the elongation of fatty acids required for mycolic acid synthesis (Vilchèze & Jacobs, 2007). Delamanid and pretomanid inhibit the synthesis of specific mycolic acid subclasses, such as methoxy- and keto-mycolic acids, leading to cell wall destabilization (Stover et al., 2000). Other inhibitors target beta-ketoacyl-ACP synthases (KasA/B) or the transporter MmpL3, which is required for mycolic acid export (North et al., 2014).