Mécanismes d'action et de résistance de l'isoniazide, un antituberculeux de première ligne

Isoniazid is the most widely used antituberculosis drug since the recognition of its clinical activity against Mycobacterium tuberculosis in the early 1950s. It has a powerful bactericidal activity against M. tuberculosis. It is a prodrug that is activated by the enzyme KatG of M. tuberculosis, a catalase-peroxidase. The main target of isoniazid is the protein InhA, an enoyl-acyl carrier protein reductase belonging to the system of fatty acid elongation FAS-II involved in mycolic acid biosynthesis. Isoniazid inhibits the synthesis of mycobacterial cell wall, causing cell death. The mechanisms of isoniazid resistance are particularly complex because they involve several genes. About 80% of isoniazid-resistant strains carry mutations or partial or complete deletions of katG gene, the mutation Ser315Thr being found in ∼70% of the strains and providing a high level of isoniazid resistance. Fifteen to 35% of strains have a mutation in the inhA promoter, mostly in −15c→t, and 0-5% of strains in the inhA gene itself, these mutations resulting in a low level of isoniazid resistance. Less than 5% of isoniazid-resistant strains have no mutations in KatG, InhA or its promoter.