34 Tuberculosis Drugs Duncan Flashcards Preview

Thera VII > 34 Tuberculosis Drugs Duncan > Flashcards

Flashcards in 34 Tuberculosis Drugs Duncan Deck (46):

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


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


What are the Nicotinamide analogues?

Isoniazid, Ethionamide, Pyrazinamide


Which drug is this?

Q image thumb



Which drug is this?

Q image thumb



Which drug is this?

Q image thumb



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


What is the general structure of Mycobacterial Cell Walls?

A image thumb

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)


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


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

A image thumb

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


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

A image thumb

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


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


What is the Specificity of Isoniazid like?

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


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


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)


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


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


What is the MOA of Pyrazinamide?

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


What are the general characteristics of Rifampin?

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


What is the structure of Rifampin like?

Highly substituted derivative of Naphthalene. Mainly a polyketide

A image thumb

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)


What is resistance to Rifampin like?

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


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


What is the structure of Fidaxomicin like?

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


What is the MOA of Fidaxomicin?

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


What is some general info on Ethambutol?

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


What is the structure of Ethambutol?

SAR: Distance between 2 nitrogens is critical

A image thumb

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


What is Cycloserine?

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

A image thumb

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

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


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)


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


What are the general treatment outlines for Leprosy?

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


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)


What are Sulfones?

Anti-leprosy agents. Inhibits folate synthesis by antagonizing PABA

A image thumb

What is Clofazimine?

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

A image thumb

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



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

The phosphate linker in NAD


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



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

NAG-NAM crosslinked w/ DAP


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



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

Glucosamine-NAC. Peptidoglycan