34 Tuberculosis Drugs Duncan Flashcards
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?
Isoniazid
Which drug is this?
Ethionamide
Which drug is this?
Pyrazinamide
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?
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?
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?
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
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
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
What is Aminosalicylic Acid?
Specific for M. tuberculosis. Competitive with PABA. Effectiveness of PABA inhibitors differs with bacterial species. Supplanted by ethambutol
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
What is Clofazimine?
Anti-Leprosy Agent. “Plate-like” central region. Weak activity alone; used in combination. Pancake stack of DNA bases
Which antibiotic is most similar to Rifampin in terms of its own biosynthesis?
Erythromycin
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?
Linezolid
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?
Arabinan
What is the galactan portion of the cell wall attached to?
Glucosamine-NAC. Peptidoglycan
