34 Tuberculosis Drugs Duncan Flashcards Preview

Thera VII > 34 Tuberculosis Drugs Duncan > Flashcards

Flashcards in 34 Tuberculosis Drugs Duncan Deck (46):
1

What is some general information on Isoniazid (INH)?

Primary agent (resistance develops rapidly, always used in combo with other agents). Multidrug therapies. If resistant to INH + RIF + Etham, even more can be added

2

What are some reasons for multidrug therapies?

Drug resistance. TB microbe lives in relatively inaccesible places, more than one locale. Each agent can only penetrate to a part of the places TB lives. Combinations are required to cover all the locales

3

What are the Nicotinamide analogues?

Isoniazid, Ethionamide, Pyrazinamide

4

Which drug is this?

Q image thumb

Isoniazid

5

Which drug is this?

Q image thumb

Ethionamide

6

Which drug is this?

Q image thumb

Pyrazinamide

7

What is the MOA of Isoniazid?

Targets the InhA gene (involved in mycolic acid formation; mutation leads to resistance). Targets mycobacterial cell wall (unique structure in mycobacteria, mycolic acids, therefore good target). INH is a prodrug; when activated it forms an adduct with nicotinamide

8

What is the general structure of Mycobacterial Cell Walls?

A image thumb
9

What are Mycolic Acids?

Very long chain, alpha-branched, epoxide-containing fatty acids (long chain is 40-60 C, short chain 20-24 C). Biosynthesis: like fatty acids (elongation involves series of enzymes). InhA encodes elongation enzyme (Isoniazid blocks elongation)

10

What are the characteristics of the InhA Protein?

Enoyl acyl carrier protein (ACP) reductase. REQUIRES Nicotine Adenine Dinucleotide (NADH) to reduce a double bond in the C-C chain

11

What are the steps in Isoniazid forming an adduct with Nicotinamide?

A image thumb
12

What are the binding pockets of InhA like?

Has two binding pockets: substrate and cofactor. INH bound do NAD can fit this pocket, inhibiting InhA's function

13

What are two very important partners and cofactors that are required in order for Isoniazid to link with NADH?

A image thumb
14

What can happen with Catalase mutantations?

Catalase mutants (KatG) were among the first characterized to lead to INH resistance. Catalase mutants are the single greatest basis for INH resistance in clinical samples

15

What is the metabolism of Isoniazid like?

Metabolized by acetylation. Polymorphism affects acetylation rate, such that certain (fast-metabolizers) achieve lower drug concentration. Acetylated product can be hydrolyzed to yield acetylhydrazine, a liver toxin

16

What is the Specificity of Isoniazid like?

Unique target: Mycobacterial cell wall, Mycolic acnd and InhA. Mycobacterial-specific activation of Isoniazid (requires InhA)

17

What are the factors affecting resistance development?

1) Slow division (> 24hrs).  2) Catalase activity (reduced --> resistance). 3) InhA mutations; ser94 to alanine. 4) Mutation rate accelerated by drug treatment. 5) Immune compromised individuals

18

How does Slow Division (> 24hrs) lead to resistance development against Isoniazid?

Makes rapid identification difficult. Rate of "killing" proportional to rate of division, therefore: greater time to develop resistance (especially if complete treatment regimen is not followed through)

19

How is the Mutation Rate accelerated by drug treatment, leading to Isoniazid resistance?

DNA damage (e.g. macrophage attack) induces novel DNA polymerase (dnaE2). dnaE2 is an "error-prone polymerase": leads to increased frequency genome-wide mutations. Some, by chance, will lead to drug resistance

20

What are some other unique cell wall features of Mycobacteria?

Trehalose mycolate (attachment of mycolic acid to arabinoglycan). Diaminopimelic Acid (required in cross-linking reaction, its biosynthesis represents potential therapeutic target). Both compounds, pathways, unique

21

What is the MOA of Pyrazinamide?

Prodrug. Activated Pyrazinamidase: forms pyrazinoic acid, causes cellular acidification and cell death

22

What are the general characteristics of Rifampin?

Class of agents called Rifamycins. Active against Gram (+), Mycobacteria, Gram (-) (poorer penetration thoug). Either bacteriostatic or bactericidal

23

What is the structure of Rifampin like?

Highly substituted derivative of Naphthalene. Mainly a polyketide

A image thumb
24

What is the general process affected by Rifampin?

Inhibits RNA biosynthesis by inhibiting the INITIATION phase. Affects all bacteria; targets B-subunit of RNA polymerase, which is similar in all bacteria. Doesn't affect humans (our RNA polymerase is substantially different)

25

What is resistance to Rifampin like?

Resistance is relatively common in the "wild". Most d/t mutated Beta subunit

26

What is Fidaxomicin?

Specifically used for treating C. difficile antibiotic-associated diarrhea (CDAD). Greater cause of nosocomial infectious death than MRSA. Very narrow spectrum of activity. PRESERVES normal intestinal flora. Low plasma levels, minimizes ADRs

27

What is the structure of Fidaxomicin like?

Large 18 atom ring. Sugars at C12 and 21. Poorly soluble in water

28

What is the MOA of Fidaxomicin?

Inhibits RNA polymerase. Blocks the initiation phase. Mechanism is distinct from RIF, so there is no overlapping resistance

29

What is some general info on Ethambutol?

Combined with Rifampin, Isoniazid. Resistance rare in natural populations. Fewer side effects, resistance compared with aminosalicylic acid

30

What is the structure of Ethambutol?

SAR: Distance between 2 nitrogens is critical

A image thumb
31

What is the MOA of Ethambutol?

Ethambutol influences cell wall biosynthesis. Specifically, it blocks synthesis of the arabinogalactan. Overexpression of the arabinosyl transferase gene EmbAB confers resistance

32

What is Cycloserine?

Inhibits alanine synthetase, alanine racemase. Competitive with D-alanine. Blocks cell wall synthesis

A image thumb
33

What is Aminosalicylic Acid?

Specific for M. tuberculosis. Competitive with PABA. Effectiveness of PABA inhibitors differs with bacterial species. Supplanted by ethambutol

A image thumb
34

What is Diarylquinones?

Identified an active compound from library. Identified target via mutagenesis, genome sequencing of resistant mutants. Inhibits the C-subunit of ATP synthase

35

What is an example of how Benzothiazinones were discovered?

Need for new agents. 1) Identification (chemical library, hit structural classes identified). 2) Medicinal Chemistry: SAR (sulfur and nitro required; S vs. R at chiral center not important; amino derivatives INACTIVE). 3) Pharmaceutical efficacy (cell culture and animal infection models). 4) Drug targets: identification (resuce from drug toxicity, resistance-conferring genes). 5) MOA (inferred molecular pathway/proteins, biochemical validation)

36

What does Leprosy manifest as?

Caused by Mycobacterium leprae. Simple, single lesions; multiple lesions; in bad cases, as "rotting" extremities. Rarely fatal in and of itself

37

What are the general treatment outlines for Leprosy?

Least severe (Paucobacillary (PB)): Rifampin + Dapsone. More severe (Multibacillary (MB)): Rifampin + Dapsone + Clofazimine

38

What are the different treatment timelines for Leprosy?

1 dose ROM (Rifampin + Ofloxacin + Minocycline) vs. 6-12 months Rx. Single agent therapy should be considered unethical (resistance "always" develops, leading to therapy failure)

39

What are Sulfones?

Anti-leprosy agents. Inhibits folate synthesis by antagonizing PABA

A image thumb
40

What is Clofazimine?

Anti-Leprosy Agent. "Plate-like" central region. Weak activity alone; used in combination. Pancake stack of DNA bases

A image thumb
41

Which antibiotic is most similar to Rifampin in terms of its own biosynthesis?

Erythromycin

42

What does the serine residue in InhA that is frequently mutated in resistant strains bind to?

The phosphate linker in NAD

43

In terms of molecular MOA, which Abx is Rifampin most similar to?

Linezolid

44

What is the peptidoglycan portion of the mycobacterial cell wall composed of?

NAG-NAM crosslinked w/ DAP

45

What is the mycolic acid portion of the cell wall attached to?

Arabinan

46

What is the galactan portion of the cell wall attached to?

Glucosamine-NAC. Peptidoglycan