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CDC isoniazid mechanism mycolic acid KatG InhA tuberculosis

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isoniazid AND tuberculosis

The slides explain isoniazid (INH), a first-line anti-tuberculosis medicine.

What is isoniazid?

  • Full chemical name: isonicotinic acid hydrazide
  • It is a small, water-soluble drug used against susceptible Mycobacterium tuberculosis.
  • It is especially active against rapidly dividing TB bacilli.
  • It penetrates macrophages well, so it can act on TB organisms both:
    • outside cells (extracellular), and
    • inside macrophages (intracellular).
It has much less activity against many nontuberculous or atypical mycobacteria.

Meaning of “bactericidal”

At low concentrations, INH kills actively multiplying TB bacilli rather than merely stopping their growth. This is why it has strong early activity in TB treatment. It must be used with other TB medicines, not as single-drug therapy for active TB, because resistance can develop quickly.

Mechanism of action

The key target is the mycobacterial cell wall.
The TB cell wall has layers:
  1. Cell membrane
  2. Peptidoglycan
  3. Arabinogalactan
  4. Mycolic acids
  5. Mycosides and other outer lipids
Mycolic acids are long-chain fatty acids that make the TB wall waxy, tough, and poorly permeable. They are essential for the organism's survival.
INH works in these steps:
  1. INH enters the TB bacillus as an inactive prodrug.
  2. The bacterial enzyme KatG, a catalase-peroxidase, activates it.
  3. Activated INH forms an INH-NAD adduct that inhibits InhA, an enzyme required for mycolic-acid synthesis. It may also affect KasA, involved in mycolic-acid elongation.
  4. The bacillus cannot make adequate mycolic acid.
  5. Its cell wall becomes defective, leading to death of actively growing organisms.
So, in one line:
Isoniazid is activated by KatG and blocks mycolic-acid synthesis, weakening the mycobacterial cell wall and killing growing TB bacilli.
This matches pharmacology texts: INH is a KatG-activated prodrug that targets InhA and related mycolic-acid synthesis enzymes. - Lippincott Illustrated Reviews: Pharmacology, section “Isoniazid,” lines 5550-5560. The CDC discussion of INH resistance also describes inhibition of mycolic-acid biosynthesis.

Important correction to the diagram

The diagram correctly shows:
  • INH inhibits mycolic-acid synthesis
  • Ethambutol inhibits arabinogalactan synthesis
They act at different parts of the mycobacterial cell wall.

Resistance

Common resistance mechanisms are:
  • katG mutation: INH cannot be activated.
  • inhA mutation or overexpression: the target enzyme is altered or produced in excess.
A practical memory aid:
KatG activates INH; InhA is inhibited by INH; mycolic acid is not made.
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