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

• Published in: Molecular microbiology 2015-10, Vol.98 (1), p.7-16
• Main Authors: Nataraj, Vijayashankar, Varela, Cristian, Javid, Asma, Singh, Albel, Besra, Gurdyal S., Bhatt, Apoorva
• Format: Article
• Language: English
• Subjects: Antitubercular Agents - pharmacology; Bacterial Proteins - metabolism; Biosynthesis; Cell walls; Cells; Cytoskeleton; Drug development; Drug Discovery; Enzymes; Fatty Acid Synthases - metabolism; Fatty acids; Fatty-acid synthase; Global health; Gram-positive bacteria; Lipids; Membrane Transport Proteins - metabolism; MicroReview; Multidrug resistance; Mycobacterium tuberculosis - chemistry; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - metabolism; Mycobacterium tuberculosis - pathogenicity; Mycolic acids; Mycolic Acids - chemistry; Mycolic Acids - metabolism; Ordination; Public health; Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - microbiology; Virulence
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.13101

Summary 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. 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. We discuss recent advances including the potential role of specialised fatty acid synthase complexes, a recently described mycolic acid transporter MmpL3, mycolic acids in the context of the bacterial cytoskeleton, and their role beyond maintaining cell envelope integrity.