Mycobacterial cell envelope + RNA polymerase

Category: catabolism

Overview

Mycobacterial pharmacology is its own world — the waxy mycolic-acid cell envelope is impermeable to most antibiotics. The standard RIPE regimen for active TB: rifampin (RNA polymerase β-subunit, rpoB), isoniazid (KatG-activated → mycolic acid synthesis InhA inhibition), pyrazinamide (acidic-pH-dependent activation → membrane disruption), ethambutol (arabinosyl transferase, arabinogalactan synthesis). Rifampin is also a profound CYP3A4 + P-gp inducer (DDI perpetrator hot spot — authored Wave 2a v1.1 for buprenorphine + oxycodone). Rifabutin is a rifampin analog with somewhat less induction (used in HIV co-treatment when PI/INSTI DDIs are limiting). Rifaximin (gut-only rifamycin) is non-systemic and used for hepatic encephalopathy + traveler's diarrhea — local-acting despite the rifamycin class membership.

Organ Systems

• immune-hematologic
• respiratory

Pathway Steps

1. mycolic-acid-precursor → mycolic-acid — via InhA (enoyl-ACP reductase) reduces precursor; INH-NAD adduct blocks this step. Mycobacteria build a unique, waxy envelope rich in mycolic acids — long-chain fatty acids essential for survival and impermeability. Isoniazid (via InhA) and ethambutol target mycolic-acid/arabinogalactan synthesis; this envelope is also why TB is intrinsically hard to treat.
2. mycobacterial-rna-polymerase → mycobacterial-mrna — via rifamycins bind β-subunit (rpoB) → transcription initiation arrest. Mycobacterial RNA polymerase transcribes the genes for survival and replication. Rifampin binds its β-subunit (rpoB) to block transcription — a cornerstone TB drug, with rpoB mutations the main cause of rifampin resistance and a marker of multidrug-resistant TB.

Known Modulators

• isoniazid (inhibitor) — InhA (mycolic acid synthesis, KatG-activated prodrug). TB first-line; hepatotoxicity + pyridoxine-deficiency neuropathy (B6 supplementation routine); CYP2E1 inhibitor; NAT2 polymorphic acetylation (fast/slow phenotypes)
• ethambutol (inhibitor) — arabinosyl transferase (arabinogalactan synthesis). TB first-line; optic neuritis dose-related (color-vision testing during treatment)
• pyrazinamide (inhibitor) — membrane disruption (acidic-pH-activated). TB first-line; uricemia (URAT1 inhibition); hepatotoxicity adds to INH risk
• rifabutin (inhibitor) — mycobacterial RNA polymerase β-subunit. rifamycin; less CYP3A4 induction vs rifampin (~40% lower); preferred with HIV PIs; uveitis at high doses
• rifaximin (inhibitor) — mycobacterial/enterobacteriaceal RNA polymerase β-subunit. non-absorbed rifamycin; hepatic encephalopathy + IBS-D + traveler diarrhea; local-acting in gut (no systemic CYP induction)

References

• PMID 23425167
• PMID 22828481