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

Abstract

SummaryMycolic acids are unique long chain fatty acids found in the lipid‐rich cell walls of mycobacteria including the tubercle bacillus M ycobacterium 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.

Mycolates of Mycobacterium tuberculosis modulate the flow of cholesterol for bacillary proliferation in murine macrophages

“…These findings suggest separate important roles for keto and methoxy oxygenated MA classes in manipulating the host macrophage response during the establishment of TB. This new insight may assist in deciphering and targeting the Achilles' heel of the tubercle bacillus according to an approach recently reviewed by Nataraj et al (61), relying on the most recent understanding of how MA is synthesized and differentiated into classes by Mtb. Cyclopropanation provides the minimum functionalization associated with MA virulence (17).…”

The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow‐growing mycobacteria

“…Mycolic acids can be found covalently linked to cell wall arabinogalactan and as part of the glycolipids' trehalose monomycolate (TMM), trehalose dimycolate and glucose monomycolate. They are essential for mycobacterial viability (Marrakchi et al, ; Nataraj et al, ) and virulence and are synthesised by a complex array of enzymes that includes a mammalian‐like Fatty Acid Synthase I (FAS‐I), and a multienzyme complex of Fatty Acid Synthase‐II (FAS‐II) (Marrakchi et al, ). One of the late stages of mycolic acid biosynthesis involves the Claisen condensation of a FAS‐II‐derived long meromycolate chain (C 42 ‐C 62 ) with a short FAS‐I‐derived fatty acid (C 24 ‐C 26 ) to yield α‐alkyl, β‐keto fatty acid intermediate, catalysed by the polyketide synthase Pks13 (Gande et al, ; Portevin et al, ).…”

Crystal structure of the essential biotin‐dependent carboxylase AccA3 from Mycobacterium tuberculosis

“…The bacterium has one of nature's most elaborate lipid metabolisms, which produces a complex and unique cell wall, that is also key to its virulence and inherent drug resistance. It is thus a primary drug target for current and future drugs 2, 3, 4, 5.…”