Mycolic acids: deciphering and targeting the Achilles' heel of the tubercle bacillus

Abstract

Mycolic acids are unique long chain fatty acids found in the lipid-rich cell walls of mycobacteria including the tubercle bacillus Mycobacterium tuberculosis. Essential for viability and virulence, enzymes involved in the biosynthesis of mycolic acids represent novel targets for drug development. This is particularly relevant to the impact on global health given the rise of multidrug resistant and extensively drug resistant strains of M. tuberculosis. In this review, we discuss recent advances in our understanding of how mycolic acid are synthesised, especially the potential role of specialised fatty acid synthase complexes. Also, we examine the role of a recently reported mycolic acid transporter MmpL3 with reference to several reports of the targeting of this transporter by diverse compounds with anti-M. tuberculosis activity. Additionally, we consider recent findings that place mycolic acid biosynthesis in the context of the cell biology of the bacterium, viz its localisation and co-ordination with the bacterial cytoskeleton, and its role beyond maintaining cell envelope integrity.

Figure 1

A. Fundamental structure of a mycolic acid shown using M . tuberculosis α‐mycolic acid as an example. B. Structures of other mycolic acid subclasses from M . tuberculosis.

Figure 2

Schematic illustrating the biosynthesis pathway for mycolic acids in M . tuberculosis in the context of proposed specialised FAS‐II complexes. R1; C ₁₆–C ₁₈, R2; C ₂₄–C ₂₆, R3 represents a range of intermediate length meroacyl chains, R4 represents a range of longer meroacyl chains, R5 is the longest meroacyl chain. I‐FAS‐II; initiator FAS‐II, T‐FAS‐II; termination FAS‐II, and E1‐FAS‐II and E2‐FAS‐II represent elongation complexes.