What is the mechanism of action (Moa) of Isoniazid (Isonicotinic Hydrazide)?

From the Guidelines

Isoniazid's mechanism of action involves inhibiting mycolic acid synthesis in mycobacteria, particularly Mycobacterium tuberculosis, by inhibiting the enzyme InhA (enoyl-ACP reductase) after being activated by the bacterial enzyme catalase-peroxidase (KatG) 1.

Mechanism of Action

The drug works as a prodrug that requires activation by the bacterial enzyme catalase-peroxidase (KatG), which converts isoniazid into its active form. Once activated, isoniazid inhibits the enzyme InhA (enoyl-ACP reductase), which is essential for the synthesis of mycolic acids, key components of the mycobacterial cell wall.

Effect on Mycobacteria

Without these mycolic acids, the cell wall structure is compromised, leading to increased permeability, disruption of cellular functions, and ultimately bacterial death. This selective toxicity makes isoniazid particularly effective against mycobacteria while having minimal effects on human cells.

Clinical Use

Isoniazid is a cornerstone drug in tuberculosis treatment, typically used in combination with other antimycobacterial agents like rifampin, ethambutol, and pyrazinamide to prevent resistance development.

Important Considerations

When prescribing isoniazid, supplementation with vitamin B6 (pyridoxine) at 25-50 mg daily is recommended to prevent peripheral neuropathy, a common side effect resulting from the drug's interference with pyridoxine metabolism 1. Some key points to consider when using isoniazid include:

• The potential for hepatotoxicity, which is more common in adults than children 1
• The importance of directly observed therapy (DOT) when administering isoniazid intermittently (i.e., twice weekly) 1
• The need to rule out active TB before beginning treatment of latent TB infection (LTBI) 1

From the FDA Drug Label

Mechanism of Action Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacteri- al cell wall The mechanism of action of isoniazid is the inhibition of mycolic acid synthesis, which is an essential component of the bacterial cell wall.

• Isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms at therapeutic levels 2.

From the Research

Mechanism of Action of Isoniazid

• Isoniazid (INH) is a pro-drug that is activated by catalase-peroxidase (KatG) to form reactive species that inhibit mycolic acid synthesis 3, 4, 5, 6
• The activated form of INH reacts with NAD(+) and NADP(+) to form adducts that are potent inhibitors of lipid and nucleic acid biosynthetic enzymes 3, 5
• The primary target of INH is the inhA-encoded, NADH-dependent enoyl acyl carrier protein reductase (InhA) 3, 6
• INH also inhibits other enzymes, including beta-ketoacyl ACP synthase (KasA) and arylamine N-acetyltransferases (NATs) 3

Key Enzymes Involved in Isoniazid Action

• KatG: catalase-peroxidase that activates INH 3, 4, 5, 6
• InhA: NADH-dependent enoyl acyl carrier protein reductase that is the primary target of INH 3, 6
• KasA: beta-ketoacyl ACP synthase that is inhibited by INH 3
• NATs: arylamine N-acetyltransferases that inactivate INH 3

Resistance Mechanisms

• Mutation in the katG gene is the major cause of INH resistance 3
• Mutations in the inhA gene can also confer resistance to INH 3, 6
• Increased expression of InhA or mutations that lower the enzyme's affinity to NADH can also lead to resistance 6
• Defects in NADH dehydrogenase (Ndh) of the respiratory chain can also confer resistance to INH 6