Antimycobacterial agents medchem Flashcards
What activates isoniazid?
KatG (catalase-peroxidase)
What is the MoA of activated isoniazid?
- Inhibits InhA
- This blocks mycolic acid synthesis
- Causes defective cell wall
What is InhA and why is inhibiting it important?
- A component of FAS II
- Catalyzes the NADH-dependent reduction of FAs bound to acyl carrier protein
What can cause resistance to isoniazid?
Over-expression of InhA
How to reverse isoniazid toxicity?
Pyridoxine
What is the MoA of pyrazinamide?
Inhibition of panD that causes panD degradation and then inhibition of coenzyme A synthesis
What can cause resistance to pyrazinamide?
Mutations in pncA
What is the MoA of ethambutol?
- Inhibits mycobacterial arabinosyl transferases
- Inhibits formation of arabinogalactan and lipoarabinomannan (LAM)
What is the MoA of rifampin?
Binds to RNA polymerase deep within DNA/RNA channel which blocks the path of elongating RNA
What is the MoA of bedaquiline?
Inhibits ATP synthase
What is structurally important for the MoA of the nitroimidazoles (pretomanid and delamanid)?
The nitrogens at the end of the structure
What activates pretomanid?
M. tb deazaflavin-dependent nitroreductase (Ddn)
What is the MoA of pretomanid in aerobic conditions?
Forms reactive intermediate metabolite that inhibits mycolic acid production
What is the MoA of pretomanid in anaerobic, nonreplicating, and persistent bacilli conditions?
- Generates reactive N species, like NO
- Depletes ATP by poisoning respiratory complex
- Increases killing by innate immune system
