EXAM 5 TB

Question 1

Mycobacterium tuberculosis

Answer 1

slow-growing aerobic bacterium - relatively resistant to most antitbiotics

neither gram negative or positive

Question 2

Treatment of TB infections

Answer 2

Most common: combo of riframpin, isoniazid, pyrazinamide, and ethambutol (RIPE)

Alternative: rifapentine, isoniazid, pyrazinamide, moxifloxacin

multiple drugs to combat dividing/dormant forms

Question 3

Isoniazid (Isonicotinic acid hydrazide) MOA

Answer 3

prodrug - activated by KatG
inhibits NAD+ and NADP+ (enzyme cofactors)

activated isoniazid:
inhibits Inha, which is component of FAS 2
catalyzes NADH-dependent reduction FAs
blocks mycolic acid synthesis –> defective cell wall

Question 4

isoniazid resistance

Answer 4

Overexpression of InhA

Question 5

isoniazid metabolism

Answer 5

acetylation by liver N-acetyltransferase (NAT2)

Question 6

Isoniazid toxicity

Answer 6

Hepatitis: due to conversion of hepatometabolite

peripheral neuropathy: resembles pyridoxine (B6) and inhibits pyridoxine phosphokinase –> reversed by admin of pyridoxine

Question 7

Pyrazinamide MOA

Answer 7

prodrug requires pncA

Inhibition of panD leading to inhibition of Coenzyme A synthesis

Question 8

Pyrazinamide Resistance

Answer 8

Primarily due to mutations in pncA

Question 9

Pyrazinamide Toxicity

Answer 9

Joint pain and hepatitis

Question 10

Ethambutol
MOA
Resistance
Toxicity

Answer 10

Synergistic with rifampin

Resistance: over-expression of or mutations in arabinosyl transferase

Toxicity: optic neuritis

Question 11

Rifampin MOA

Answer 11

Semisynthetic derivative of rifamycin B

MOA: binds to RNA polymerase deep within DNA/RNA channel

Bactericidal

Question 12

Fluoroquinolones MOA

Answer 12

Traps gyrase on DNA as ternary complex

Prevents resolution of supercoiled DNA

Disrupts DNA replication

Bactericidal

Question 13

Toxicity associated with anti-Tb drugs

Answer 13

Hepatitis: Isoniazid, pyrazinamide, rifampin
Eye damage: ethambutol
Orange discolartion in urine: rifampin

Question 14

BPaL regimen

Answer 14

bedaquiline
pretomanid
linezolid

Question 15

Bedaquiline
MOA
metabolism
resistance

Answer 15

MOA: inhibis ATP synthase

Metabolism: CYP3A4

Resistance: mutations in atp

Question 16

Nitroimidazoles: pretomanid MOA

Answer 16

prodrug
Contains nitro groups

Aerobic conditions: forms intermediate metabolite that inhibits mycolic acid production

Anaerobic conditions: generates reactive nitrogen species such as NO, which poisons respiratory complex and leads to ATP depletion

Question 17

Second line agents

Answer 17

Have activity against TB, but not really used as much bc of toxicity

Only used when there is resistance to 1st line treatment

• Streptomycin
• Ethionamide
• Para-aminosalicylic acid
• Cycloserine: analog D-ala
• Capreomycin