Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Tuberculosis (TB) remains a global health crisis, exacerbated by multidrug-resistant strains and treatment complexities.
• Current TB therapies often face challenges including resistance and the need for prolonged treatment regimens.
• The mycobacterial cell wall is a critical target for anti-TB drug development.

Purpose of the Study:

• To comprehensively review approved drugs targeting Mycobacterium tuberculosis cell wall biosynthesis.
• To elucidate the molecular mechanisms of action for these established and investigational TB drugs.
• To highlight advancements in novel cell wall-targeting therapies currently in clinical development.

Main Methods:

• Literature review of approved anti-TB drugs and their mechanisms.
• Analysis of molecular targets within the mycobacterial cell wall biosynthesis pathways.
• Survey of investigational drugs in Phase II clinical trials targeting cell wall synthesis.

Main Results:

• Five approved drugs target cell wall biosynthesis: isoniazid, thioamides, delamanid (mycolic acid synthesis; delamanid also affects arabinogalactan synthesis).
• Cycloserine inhibits peptidoglycan synthesis; ethambutol targets arabinogalactan synthesis via arabinosyl transferases.
• Six novel agents (sutezolid, TBA 7371, OPC-167832, SQ109, BTZ043, PBTZ169) are in Phase II trials, targeting arabinan synthesis.

Conclusions:

• Existing drugs target key mycobacterial cell wall components, but resistance necessitates new strategies.
• Delamanid exhibits a dual mechanism, impacting both mycolic acid and arabinogalactan pathways.
• Advancements in targeting cell wall synthesis, particularly arabinan pathways, show promise for future TB treatments.