34 Tuberculosis Drugs Duncan Flashcards

1
Q

What is some general information on Isoniazid (INH)?

A

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

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2
Q

What are some reasons for multidrug therapies?

A

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

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3
Q

What are the Nicotinamide analogues?

A

Isoniazid, Ethionamide, Pyrazinamide

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4
Q

Which drug is this?

A

Isoniazid

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5
Q

Which drug is this?

A

Ethionamide

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6
Q

Which drug is this?

A

Pyrazinamide

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7
Q

What is the MOA of Isoniazid?

A

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

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8
Q

What is the general structure of Mycobacterial Cell Walls?

A
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9
Q

What are Mycolic Acids?

A

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)

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10
Q

What are the characteristics of the InhA Protein?

A

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

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11
Q

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

A
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12
Q

What are the binding pockets of InhA like?

A

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

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13
Q

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

A
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14
Q

What can happen with Catalase mutantations?

A

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

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15
Q

What is the metabolism of Isoniazid like?

A

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

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16
Q

What is the Specificity of Isoniazid like?

A

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

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17
Q

What are the factors affecting resistance development?

A

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

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18
Q

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

A

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)

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19
Q

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

A

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
Q

What are some other unique cell wall features of Mycobacteria?

A

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
Q

What is the MOA of Pyrazinamide?

A

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

22
Q

What are the general characteristics of Rifampin?

A

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

23
Q

What is the structure of Rifampin like?

A

Highly substituted derivative of Naphthalene. Mainly a polyketide

24
Q

What is the general process affected by Rifampin?

A

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
Q

What is resistance to Rifampin like?

A

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

26
Q

What is Fidaxomicin?

A

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
Q

What is the structure of Fidaxomicin like?

A

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

28
Q

What is the MOA of Fidaxomicin?

A

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

29
Q

What is some general info on Ethambutol?

A

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

30
Q

What is the structure of Ethambutol?

A

SAR: Distance between 2 nitrogens is critical

31
Q

What is the MOA of Ethambutol?

A

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

32
Q

What is Cycloserine?

A

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

33
Q

What is Aminosalicylic Acid?

A

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

34
Q

What is Diarylquinones?

A

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

35
Q

What is an example of how Benzothiazinones were discovered?

A

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
Q

What does Leprosy manifest as?

A

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

37
Q

What are the general treatment outlines for Leprosy?

A

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

38
Q

What are the different treatment timelines for Leprosy?

A

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
Q

What are Sulfones?

A

Anti-leprosy agents. Inhibits folate synthesis by antagonizing PABA

40
Q

What is Clofazimine?

A

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

41
Q

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

A

Erythromycin

42
Q

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

A

The phosphate linker in NAD

43
Q

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

A

Linezolid

44
Q

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

A

NAG-NAM crosslinked w/ DAP

45
Q

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

A

Arabinan

46
Q

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

A

Glucosamine-NAC. Peptidoglycan