Mycobacterium (MC) - Block 3

Question 1

What are the sx of TB?

Answer 1

Productive cough, fatigue, night sweats

Question 2

How do you diagnose TB?

Answer 2

Identification of organism
Chest x-ray
Tubercilin test

Question 3

Sx of leprosy?

Answer 3

Anesthetic or paresthetic patches
Mucle atrophy
Bone resorption
Blindness

Question 4

Diagnosis for leprosy?

Answer 4

Skin smear
ANtibody detection

Question 5

What are the pools of mycobacterium?

Answer 5

1. Extracellular
2. Intracellular
3. Necrotic pool with macrophages

Question 6

Does prior exposure to TB protect someone from getting it a second time?

Answer 6

No

Question 7

What is latency?

Answer 7

Capable of reactivating later and much harder to kill

Question 8

What are drugs used for TB?

Answer 8

1. Rifampin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol

Question 9

Why is mycobacterium cell wall complex?

Answer 9

High lipid content and very complicated

Question 10

How does FA synthesis occurs?

Answer 10

inhA (enoyl reductase) reduces acyl carrier protein (alkene) with the help of cofactor (NADH)

Question 11

MOA of isoniazid?

Answer 11

Prodrug inhibitor of mycolic acid biosynthesis:
* acylated NADH not able to reduce alkene in fatty acid synthesis -> blocking mycolic acid synthesis

Question 12

What is the endogenous substate mimiced by isoniazid?

Answer 12

Nicotinic acid

Question 13

How is INH metabolized?

Answer 13

NAT (phase 2 conjugation) -> CYP450 metabolism can form an acyl radical responsible for liver necrosis

Question 14

PK of isoniazid?

Answer 14

1. Absorption is decreased in the presence of AI ion
2. Well distributed (granuloma and CSH)
3. Used alone for prophylaxis
4. Combo for infectious condition
5. Combined with B6 (pyridoxine) to reduce peripehral neuritis

Question 15

What is the ansamycin ABX?

Answer 15

Rifamycin

Question 16

MOA of ansamycin?

Answer 16

Targets bacterial DNA-directed RNA polymerase in G+

Question 17

MOA of rifampin?

Answer 17

1. Inhibits DNA-dependent RNA polymerase in bacterial cells by binding to b-subunit preventing transcription to RNA and translation to proteins
2. Interacts with b-subunit of RNA polymerase when its a a2b trimer -> halting mRNA transcription -> preventing translation of polypeptides

Doesn’t stop elongation of mRNA once bindign to template strand of DNA has been intiated

Question 18

Why is rifampin not used as a monotherapy?

Answer 18

Resistance develops quickly

Question 19

SAR of rifamycin?

Answer 19

Inhibits DNA-dependent RNA polymerase:
1. pi-pi bonding between naphthalene and aromatice amino acids of DDRP
2. Chelation to zic present in DDRP
3. H-bonding to enzyme through C21 and C23 OH

Question 20

Metabolism of rifampin?

Answer 20

Hydrolysis of Schiff base

Question 21

Describe the instability of rifampin?

Answer 21

Oxidation of parahydroxyquinone to paraquinone preventing pi-pi stacking

Question 22

ADR of rifampin?

Answer 22

1. Excretion of red-orange color
2. Hepatox and GI irritation

Question 23

DDI of rifampin?

Answer 23

CYP450 inducer (3A4 and 2C8/9/19) NOT D6

Question 24

Indication for rifaximin?

Answer 24

Traveler’s diarrhea, IBS-D

Question 25

What is the characterisitc of pyrazinamide?

Answer 25

Prodrug inhibitor of fatty acid symthesis -> Active against leten TB

Question 26

MOA of pyrazinamide?

Answer 26

Activated by pyrazibamidase to form pyrazinoic acid: * Lowers pH of media * Antimetabolite of NAD synthesis

Question 27

Indication for PZA?

Answer 27

Semidormant intracellular bacilli

Question 28

What is is the class of ethambutol?

Answer 28

Inhibitor of cell wall arabinan biosynthesis -> increases cell entry of other agents

Question 29

MOA of ethambutol?

Answer 29

Inhibits arabinosyl transferace that converts arabino to polyarbinose in AG and LAM

Question 30

ADR of ethambutol?

Answer 30

Optic neuritis with loss of visual acuity (red from green)

Question 31

What is the activity of ethionamide?

Answer 31

Activated by catalase peroxidase -> acytalates InhA or EthA leading to inhibtion of unsaturated fatty acid reduction and can produce an acyl radical

Question 32

What is PAS (para aminosalicylic acid)

Answer 32

Antimetabolte of PABA blocking folate acid synthesis

Question 33

ADR of ethionamide?

Answer 33

Hypersensitiy

Question 34

MOA of cycloserine?

Answer 34

Inhibitor of L-alanine racemase - blocks D-alanine syntheis (part of PG Mycobacterium)

Question 35

MOA of bedaquiline?

Answer 35

Breaththrough drug: * Bonds at subunit C of ATP synthase * Blocks the protein pump for ATP synthase

Question 36

What are the resistant mechanisms against bedaquiline?

Answer 36

1. Mutations of ATP synthase 2. Mutation to target: gene atpE codes of subunity 3. Mutations in drug efflux pumps

Question 37

DDI of bedaquiline? BBW?

Answer 37

CYP3A4 inhibiton **BBW:** QT prolongation from hERG channel blockage

Question 38

What is the MOA of pretomanid?

Answer 38

1. Inhibition of cell wall mycolic acid biosynthesis in aerobic cells (replicating) 2. Respiratory poisoning through NO release in anaerobic activity (static) 3. Prodrug activated by deazaflavin

Question 39

Drug combos used for MAC infection?

Answer 39

**Macrolides (choice):** Clarithromycin, Azithromycin **Rifamycins:** Refabutin **Misc:** Ethambutol, Ciprofloxacin, Clofazimine

Question 40

Drug tx for leprosy?

Answer 40

Dapsone, Clofaziminem, Thalidomide

Question 41

MOA of dapsone?

Answer 41

Inhibits PABA incorporation into folic acid -> well absorbed

Question 42

MOA of clafazimine?

Answer 42

Generates ROS fro ractive carbones

Question 43

MOA and indication of thalidomide?

Answer 43

Inhibits synthesis of TNF-a **Indication:** erythema nodosum leprosum