What is the mechanism of Isoniazid?

Isoniazid, also known as isonicotinylhydrazine (INH), is a crucial medication in the treatment of tuberculosis (TB). This antibiotic has been a frontline treatment since its discovery in the 1950s, due to its efficacy against Mycobacterium tuberculosis, the bacterium responsible for TB. Understanding the mechanism of Isoniazid provides insights into its therapeutic action and potential side effects, as well as its role in modern medicine.

Isoniazid is a pro-drug, which means it requires activation within the body to exert its effects. Once administered, Isoniazid enters mycobacterial cells through passive diffusion. Inside the bacterium, it is activated by a bacterial enzyme known as catalase-peroxidase, which is encoded by the katG gene. The activation process converts Isoniazid into reactive species, including isonicotinic acyl radicals and reactive oxygen species (ROS).

These reactive intermediates primarily target an enzyme called InhA, a component of the fatty acid synthase II (FAS-II) system in Mycobacterium tuberculosis. InhA is crucial for the synthesis of mycolic acids, which are long-chain fatty acids that make up a significant part of the mycobacterial cell wall. Mycolic acids are essential for the integrity, impermeability, and pathogenicity of the bacterial cell wall. By inhibiting InhA, the activated form of Isoniazid disrupts the synthesis of mycolic acids, leading to the weakening of the cell wall and eventually causing bacterial cell death.

The bactericidal activity of Isoniazid is particularly effective against actively dividing mycobacteria, where cell wall synthesis is most robust. This selective targeting helps in reducing the bacterial load in infected individuals. However, the drug is less effective against dormant or slowly replicating bacteria, which is why Isoniazid is often used in combination with other antitubercular drugs like rifampin, pyrazinamide, and ethambutol to ensure comprehensive treatment.

Despite its efficacy, the use of Isoniazid is not without challenges. Resistance to Isoniazid can develop through various mechanisms, the most common being mutations in the katG gene. These mutations can reduce or eliminate the bacterium's ability to activate Isoniazid, rendering it ineffective. Another resistance mechanism involves mutations in the inhA gene or its promoter region, leading to overexpression of InhA or structural changes that reduce the binding affinity of the drug.

It's also important to consider the host's metabolic response to Isoniazid. The drug is metabolized in the liver primarily through acetylation, a process mediated by the enzyme N-acetyltransferase 2 (NAT2). The rate of acetylation varies among individuals due to genetic polymorphisms in the NAT2 gene, classifying people as either slow or fast acetylators. Slow acetylators are at a higher risk of experiencing adverse effects, such as hepatotoxicity and peripheral neuropathy, due to higher plasma levels of the drug.

In conclusion, the mechanism of Isoniazid involves its activation by mycobacterial catalase-peroxidase, leading to the inhibition of mycolic acid synthesis and subsequent bacterial cell death. While highly effective, the emergence of drug resistance and variability in host metabolism present challenges that need to be addressed through combination therapy and personalized medicine approaches. Understanding these dynamics is crucial for optimizing the use of Isoniazid in the fight against tuberculosis.