Tuberculosis Flashcards
Pathogen
Mycobacterium tuberculosis
Slow-growing aerobic bacterium
Acid fast bacteria: neither gram + or -
Thick cell wall containing mycolic acids and arabinogalactan impermeable to many drugs
Resides within a phagosome that allows for a lack of degradation
Isoniazid MOA
PRODRUG
Bactericidal
Activation of KatG inside bacteria
Nicotinoyl radical forms adducts with NAD+ and NADP+
Inhibits enzymes
NAD adduct–>InhA, KasA
InhA is a component of FAS II that catalyzes the NADH-dependent reduction of fatty acids bound to acyl protein
FAS I–>C20 precursors linked to CoA–>FAS II–>C56 linked to CoA–>addition of side chain C22 or C24 and cyclopropyl–>out of cell–>links to arabinogalactan of cell wall
Result: inhibits mycolic acid synthesis
Isoniazid resistance
Mutations in KatG
Over expression of InhA
Isoniazid metabolism
Acetylation in liver N-acetyltransferase (NAT2)
Toxicity: Acetylisoniazid–>Acetylhydrazine
CYP2E1=hepatotoxic metabolites
NAT2=nontoxic metabolites
Isoniazid Side effects
Hepatitis
Peripheral neuropathy: reversed by adding pyridoxine (Vitamin B6)
- Isoniazid competitively inhibits pyridoxine phosphate reducing active form of Vitamin B6
Pyrazinamide MOA
PRODRUG
Shortened tx to 6 months
Pyrazinamide (PZA)–>PncA–>Pyrazinoic Acid (POA) + Ammonia
- neutral pH= not active
- pH < 5.5= active
POA binds panD leading degradation causing inhibition of CoA synthesis and increases free fatty acid
- panD converts aspartate to alanine
Pyrazinamide resistance
Mutation in PncA
- evidence of RpsA, panD, ClpC1
Pyrazinamide side effects
Arthralgia
Hepatitis: must undergo hepatic function test before treatment
Ethambutol MOA
Bacteriostatic
Inhibits mycobacterial arabinosyl transferases involved in polymerization or arabinogalactan–>buildup of arabinan
Ethambutol synergy
Rifampin
Ethambutol resistance
Mutation in arabinosyl transferase
Over expression of arabinosyl transferase
Ethambutol side effects
Optic neuritis–>irreversible potentially
Rifampin
Bactericidal
Claim to fame: reduced duration from 18 to 9 months
Most effective 1st line agent due to high sterilizing activity
Can kill M. tb inaccessible to many other drugs growing and stationary but most effective when cell division is occurring
Rifampin MOA
Binds allosterically to RNA polymerase within DNA/RNA channel and blocks elongating RNA
Rifampin side effects
Bodily fluids orange
Hepatitis
CYP450 inducer
Rifapentine
Cyclopentyl ring leading to high lipophilicity and longer t1/2
Fluoroquinolone’s
Moxifloxacin, gatifloxacin, levofloxacin
Bactericidal
Traps gyrase on DNA in ternary complex preventing resolution of supercoiled DNA
Bedaquiline MOA
Inhibits ATP synthase
Bedaquiline resistance
Mutation in atpE
Pretomanid
Structure: nitro-dihdro-imidazooxazole
Pretomanid MOA
activated by Ddn
Aerobic: reactive metabolite inhibiting mycolic acid production
Anaerobic: reactive nitrogen species causing direct poisoning of respiratory complex–>ATP depletion
