Mycolic Acid Biosynthesis and Mycobacterial Pathogenicity

Mycolic acids are unique long-chain α-alkyl-β-hydroxy fatty acids that form the core of the mycobacterial cell envelope, conferring remarkable impermeability and resistance to host defences and antibiotics. Their biosynthesis proceeds via two fatty acid synthase systems: FAS-I, which generates medium-chain precursors, and FAS-II, which extends these into very long meromycolate chains. Key enzymes in FAS-II include the β-ketoacyl synthases (KasA/KasB), dehydratases and reductases such as MabA, and specialised cyclopropane synthases that introduce functional modifications. The final mycolates are exported by membrane transporters and assembled into trehalose dimycolate and arabinogalactan–mycolate complexes, shaping cell-wall fluidity and host–pathogen interactions. Beyond structural integrity, mycolic acid modifications modulate immune evasion by altering cytokine responses and granuloma formation. Disruption of this pathway undermines viability and attenuates virulence, making every biosynthetic step a potential drug target and underscoring the global urgency to develop novel antitubercular agents.

Research from Nature Portfolio

Seminal structural studies have resolved the complex of the β-ketoacyl synthase KasA with a small-molecule indazole sulfonamide, providing atomic-level insights into inhibitor binding and validating KasA as a premier target for rational drug design. Complementary biochemical and in vivo assays confirmed target engagement, resistance mechanisms and efficacy in murine infection models, laying the groundwork for next-generation antimycobacterials. In parallel, investigations of a mycobacteriophage-encoded protein demonstrated its ability to perturb mycolic acid metabolism and enhance cell-wall permeability, thereby potentiating the activity of diverse antibiotics. Transcriptomic and lipidomic analyses revealed that phage protein expression triggers dysregulation of lipid biosynthesis genes and reactive oxygen species accumulation, offering a novel means to sensitise mycobacteria to existing therapies.

Mycolic Acid Biosynthesis and Mycobacterial Pathogenicity publication trend

The graph below shows the total number of articles in mycolic acid biosynthesis and mycobacterial pathogenicity across all publications each year (not limited to Nature Index journals).

Technical terms

Mycolic acids: Very long α-alkyl-β-hydroxy fatty acids that form the core lipid components of the mycobacterial cell wall.

Fatty acid synthase (FAS) systems: Enzymatic assemblies (FAS-I and FAS-II) responsible for de novo synthesis and extension of fatty acyl chains into long-chain mycolic acid precursors.

β-Ketoacyl synthase (KasA/KasB): Condensing enzymes in FAS-II that catalyse the elongation of acyl carrier protein-bound intermediates during mycolic acid chain extension.

MabA (FabG1): A 3-ketoacyl reductase in the FAS-II pathway that reduces β-ketoacyl intermediates, essential for mycolic acid biosynthesis.

MabR: A PucR-type transcription factor that regulates expression of FAS-II elongation enzymes and thus controls mycolic acid biosynthetic flux.

References

1. Exploring the Antitubercular Activity of Anthranilic Acid Derivatives: From MabA (FabG1) Inhibition to Intrabacterial Acidification. Pharmaceuticals (2023).
2. Domain architecture of the Mycobacterium tuberculosis MabR (Rv2242), a member of the PucR transcription factor family. Heliyon (2024).
3. Identification of KasA as the cellular target of an anti-tubercular scaffold. Nature Communications (2016).
4. Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against Mycobacterium via altering the cell wall permeability. Scientific Reports (2016).
5. Path‐seq identifies an essential mycolate remodeling program for mycobacterial host adaptation. Molecular Systems Biology (2019).