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)