Antimycobacterial Therapies II

Question 1

TH2-dominated responses lead to

-Extensive tissue damage with many spreading lesions which contain large numbers of bacteria

Answer 1

Lepromatous disease

Question 2

They grow as delicate branching filaments, often seen on microscopic observation of pus from a lesion

-Both tend to cause abscesses

Answer 2

Nocardia and Actinomyces

Question 3

Masses of bacteria in pus are often yellow and called

Answer 3

Sulfur granules

Question 4

Bactericidal against both extracellular and intramacrophage mycobacteria

-Small, water-soluble molecule

Answer 4

Isoniazid (INH)

Question 5

High probability of resistance (~10-6) and is almost always used with other drugs (only exception is prophylactic use)

Answer 5

INH

Question 6

Isoniazid is a pro-drug that is activated by bacterial

Answer 6

KatG

Question 7

Fatty acids are synthesized in two stages in M. tuberculosis. It uses the two enzymes

Answer 7

FAS-I and FAS-II

Question 8

A single multifunctional polypeptide that synthesizes chains up to C16–C26 using acyl-Coenzyme A (CoA) as a carrier

Answer 8

FAS-I

Question 9

A multi-enzyme system that lengthens fatty acid chains to > C52

Answer 9

FAS-II

Question 10

Fab1 (InhA) of FAS-II is the Target of

Answer 10

INH-NAD

Question 11

Fab1 (3-oxoacyl-[acyl-carrier-protein] synthase, InhA) carries out last step in the

Answer 11

FAS-II cycle

Question 12

What are two major side effects of INH?

Answer 12

Hepatitis and peripheral neuropathy

Question 13

The peripheral neuropathy caused by INH is attributable to

Answer 13

Pyridoxine deficiency

Question 14

Metabolism of INH is initiated by acetylation by the liver specific

Answer 14

N-acetyltransferase

Question 15

INH resistance can occur if there are mutations in KatG such that INH-NAD can not be

Answer 15

Formed

Question 16

A complex semi-synthetic antibiotic based on natural antibiotic (rifamycin) isolated from Streptomyces

Answer 16

Rifampin

Question 17

Prevents RNA exit from polymerase by interacting with the large (b) subunit of bacterial RNA polymerase (α2ββ’ωo) and directly blocking the path of the growing RNA

Answer 17

Rifampin

Question 18

Rifampin blocks departure of bacterial RNA polymerase (RNAP) from

Answer 18

Gene promoters

Question 19

Drug resistance to rifampin arises from mutations in the gene encoding the b subunit of

Answer 19

RNA Polymerase

Question 20

Bactericidal against fast growing extracellular mycobacteria in the lung cavity

-Also active against slow growing intracellular mycobacteria

Answer 20

Rifampin

Question 21

Penetrates cerebrospinal fluid adequately if the meninges are inflamed

Answer 21

Rifampin

Question 22

If administrated less then twice weekly – may cause flu-like symptoms (fever, chills, anemia, sometimes acute tubular necrosis, believed to be drug-allergy)

Answer 22

Rifampin

Question 23

Induces cytochrome P450 members including CYP3A => increases elimination of other drugs

Answer 23

Rifampin

Question 24

Rifampin imparts harmless purple or red color to

Answer 24

Urine, sweat, and tears

Question 25

Have a higher potency and longer half life than rifampin. Also displays better membrane permeability

Answer 25

Rifabutin & Rifapentine

Question 26

Less active in CYP3A induction (particularly rifabutin), this means a better compatibility with other medications (eg., for HIV and arrhythmia)

Answer 26

Rifabutin & Rifapentine

Question 27

Shares structurally similarity but not targeting mechanism with INH

Answer 27

Pyrazinamide (PZA)

Question 28

PZA is a pro-drug converted to active form by bacterial

Answer 28

PcnA enzyme

Question 29

Works synergistically with Rifampin -A persister killer (also called sterilizer, i.e., bacteriacidal against dormant Mtb but not replicating bacteria)

Answer 29

PZA

Question 30

To be used in combination with at least two more other drugs to avoid de facto monotherapy -Reduces chemotherapy from 9 months to 6 months

Answer 30

PZA

Question 31

Enters tubercle bacilli by passive diffusion, where it is converted to POA by PZase/nicotinamidase encoded by the pncA gene

Answer 31

PZA

Question 32

Then reaches the cell surface through passive diffusion and a weak (deficient) efflux mechanis

Answer 32

POA

Question 33

Upon stress, translating ribosomes are stalled and incomplete polypeptides may be

Answer 33

Toxic to the cell

Question 34

The bacterial cell resolves this problem by adding tmRNA to the stalled

Answer 34

mRNA

Question 35

This process is called

Answer 35

Trans-translation

Question 36

PZA inhibits

Answer 36

Trans-translation

Question 37

PZA is converted to the active form pyrazinoic acid (POA) by M. tuberculosis pyrazinamidase (Pzase), which inhibits targets including

Answer 37

RpsA

Question 38

POA binding to RpsA interferes with the interaction of RpsA with tmRNA required for

Answer 38

Trans-translation

Question 39

Blocks the EmbA and EmbB arabinosyl transfreases that incorporate arabinose into the arabinogalactan layer, thereby weakening the cell wall and making M. tuberculosis susceptible to damage

Answer 39

Ethambutol (EMB)

Question 40

Inhibits fast growing extracellular Mtb -bacteriostatic drug

Answer 40

EMB

Question 41

Oral and well absorbed from the gut (reaches blood level of 2-5 mg/ml). -50% excreted in urine unchanged

Answer 41

EMB

Question 42

What are the two major adverse side effects of EMB?

Answer 42

Optic neuritis and Red-green color blindness

Question 43

6-10% TB patients in US are

Answer 43

HIV positive

Question 44

We never want to give a twice weekly regimen during the continuation phase for a patient who has

Answer 44

HIV and TB

Question 45

If rifampin is used to treat TB in a patient with HIV than we must

Answer 45

Double or triple the retroviral drug

Question 46

Pathogens (M. avium and M. intracellulare, M. paratuberculosis and possibly other mycobacterial species) are much less susceptible than M. tuberculosis to most

Answer 46

Anti-TBs

Question 47

What are the two main antibiotics used to treat MAC infection

Answer 47

Azithromycin and clarithromycin

Question 48

A prodrug activated by EthA -Interferes with cell wall biosynthesis

Answer 48

Ethionamide (ETH)

Question 49

Active drug targets FAS-II (similarly to INH) and inhibits mycolic acid synthesis

Answer 49

ETH

Question 50

A prodrug targeting dihydrofolate synthesis

Answer 50

Para-aminosalicylic acid (PAS)

Question 51

What is the classification of PAS?

Answer 51

Bacteriostatic

Question 52

Metabolized in the gut and liver via acetylation. N-acetyl-PAS excreted by the kidney. -Short half life (1 h) requires 10-12 g/dose

Answer 52

PAS

Question 53

What are the major adverse effects of PAS?

Answer 53

GI disturbances

Question 54

Produced by soil bacteria -Structurally related to D-alanine

Answer 54

D-cycloserine

Question 55

Drug competitively inhibits alanine racemase and D-alanine ligase

Answer 55

D-cycloserine

Question 56

Second line drug with serious side effects: dose related CNS toxicity (headaches, tremors, convulsions, psychosis)

Answer 56

Cycloserine

Question 57

A 2nd line anti-TB in US, but still a 1st line drug for developing countries (WHO). -Employed for treatment of life-threatening TB forms (e.g. meningitis) & drugresistant Mycobacteria bacteria

Answer 57

Streptomycin

Question 58

Does not cross mammalian cell membrane (does not enter CNS or macrophages)

Answer 58

Streptomycin

Question 59

Amikacin, kanamycin & Capreomycin can be used for strains resistant to

Answer 59

Streptomycin