mycolic acids
Summary
Mycolic acids are very long-chain branched fatty acids that make up the waxy outer layer of the mycobacterial cell wall. They confer acid-fastness, resistance to desiccation and disinfectants, and slow growth, and their synthesis is the target of isoniazid.
Detail
Covalently linked to arabinogalactan and peptidoglycan, mycolic acids form an exceptionally impermeable hydrophobic barrier. The consequences are pervasive: mycobacteria resist Gram staining and are instead demonstrated with carbol fuchsin; they survive drying and many disinfectants, permitting airborne transmission and environmental persistence; nutrient uptake is slow, giving generation times of fifteen to twenty hours and requiring weeks of culture and months of therapy; and they resist killing within phagosomes. Cord factor (trehalose dimycolate), a mycolic acid derivative, causes serpentine cord growth in virulent strains, activates macrophages to release TNF-alpha driving granuloma formation and the constitutional symptoms of tuberculosis, and inhibits phagosome-lysosome fusion. Isoniazid is a prodrug activated by the bacterial catalase-peroxidase KatG and inhibits InhA in the mycolic acid synthesis pathway; mutations in katG are a common mechanism of isoniazid resistance. Ethionamide shares this target, and ethambutol acts nearby by blocking arabinosyltransferase.
Sources
- Levinson Medical Microbiology and Immunology
- First Aid for the USMLE Step 1
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