Antimycobacterial Therapies II Flashcards
TH2-dominated responses lead to
-Extensive tissue damage with many spreading lesions which contain large numbers of bacteria
Lepromatous disease
They grow as delicate branching filaments, often seen on microscopic observation of pus from a lesion
-Both tend to cause abscesses
Nocardia and Actinomyces
Masses of bacteria in pus are often yellow and called
Sulfur granules
Bactericidal against both extracellular and intramacrophage mycobacteria
-Small, water-soluble molecule
Isoniazid (INH)
High probability of resistance (~10-6) and is almost always used with other drugs (only exception is prophylactic use)
INH
Isoniazid is a pro-drug that is activated by bacterial
KatG
Fatty acids are synthesized in two stages in M. tuberculosis. It uses the two enzymes
FAS-I and FAS-II
A single multifunctional polypeptide that synthesizes chains up to C16–C26 using acyl-Coenzyme A (CoA) as a carrier
FAS-I
A multi-enzyme system that lengthens fatty acid chains to > C52
FAS-II
Fab1 (InhA) of FAS-II is the Target of
INH-NAD
Fab1 (3-oxoacyl-[acyl-carrier-protein] synthase, InhA) carries out last step in the
FAS-II cycle
What are two major side effects of INH?
Hepatitis and peripheral neuropathy
The peripheral neuropathy caused by INH is attributable to
Pyridoxine deficiency
Metabolism of INH is initiated by acetylation by the liver specific
N-acetyltransferase
INH resistance can occur if there are mutations in KatG such that INH-NAD can not be
Formed
A complex semi-synthetic antibiotic based on natural antibiotic (rifamycin) isolated from Streptomyces
Rifampin
Prevents RNA exit from polymerase by interacting with the large (b) subunit of bacterial RNA polymerase (α2ββ’ωo) and directly blocking the path of the growing RNA
Rifampin
Rifampin blocks departure of bacterial RNA polymerase (RNAP) from
Gene promoters
Drug resistance to rifampin arises from mutations in the gene encoding the b subunit of
RNA Polymerase
Bactericidal against fast growing extracellular mycobacteria in the lung cavity
-Also active against slow growing intracellular mycobacteria
Rifampin
Penetrates cerebrospinal fluid adequately if the meninges are inflamed
Rifampin
If administrated less then twice weekly – may cause flu-like symptoms (fever, chills, anemia, sometimes acute tubular necrosis, believed to be drug-allergy)
Rifampin
Induces cytochrome P450 members including CYP3A => increases elimination of other drugs
Rifampin
Rifampin imparts harmless purple or red color to
Urine, sweat, and tears
Have a higher potency and longer half life than rifampin. Also displays better membrane permeability
Rifabutin & Rifapentine
Less active in CYP3A induction (particularly rifabutin), this means a better compatibility with other medications (eg., for HIV and arrhythmia)
Rifabutin & Rifapentine
Shares structurally similarity but not targeting mechanism with INH
Pyrazinamide (PZA)
PZA is a pro-drug converted to active form by bacterial
PcnA enzyme
Works synergistically with Rifampin
-A persister killer (also called sterilizer, i.e., bacteriacidal against dormant Mtb but not replicating bacteria)
PZA
To be used in combination with at least two more other drugs to avoid de facto monotherapy
-Reduces chemotherapy from 9 months to 6 months
PZA
Enters tubercle bacilli by passive diffusion, where it is converted to POA by PZase/nicotinamidase encoded by the pncA gene
PZA
Then reaches the cell surface through passive diffusion and a weak (deficient) efflux mechanis
POA
Upon stress, translating ribosomes are stalled and incomplete polypeptides may be
Toxic to the cell
The bacterial cell resolves this problem by adding tmRNA to the stalled
mRNA
This process is called
Trans-translation
PZA inhibits
Trans-translation
PZA is converted to the active form pyrazinoic acid (POA) by M. tuberculosis pyrazinamidase (Pzase), which inhibits targets including
RpsA
POA binding to RpsA interferes with the interaction of RpsA with tmRNA required for
Trans-translation
Blocks the EmbA and EmbB arabinosyl transfreases that incorporate arabinose into the arabinogalactan layer, thereby weakening the cell wall and making M. tuberculosis susceptible to damage
Ethambutol (EMB)
Inhibits fast growing extracellular Mtb
-bacteriostatic drug
EMB
Oral and well absorbed from the gut (reaches blood level of 2-5 mg/ml).
-50% excreted in urine unchanged
EMB
What are the two major adverse side effects of EMB?
Optic neuritis and Red-green color blindness
6-10% TB patients in US are
HIV positive
We never want to give a twice weekly regimen during the continuation phase for a patient who has
HIV and TB
If rifampin is used to treat TB in a patient with HIV than we must
Double or triple the retroviral drug
Pathogens (M. avium and M. intracellulare, M. paratuberculosis and possibly other mycobacterial species) are much less susceptible than M. tuberculosis to most
Anti-TBs
What are the two main antibiotics used to treat MAC infection
Azithromycin and clarithromycin
A prodrug activated by EthA
-Interferes with cell wall biosynthesis
Ethionamide (ETH)
Active drug targets FAS-II (similarly to INH) and inhibits mycolic acid synthesis
ETH
A prodrug targeting dihydrofolate synthesis
Para-aminosalicylic acid (PAS)
What is the classification of PAS?
Bacteriostatic
Metabolized in the gut and liver via acetylation. N-acetyl-PAS excreted by the kidney.
-Short half life (1 h) requires 10-12 g/dose
PAS
What are the major adverse effects of PAS?
GI disturbances
Produced by soil bacteria
-Structurally related to D-alanine
D-cycloserine
Drug competitively inhibits alanine racemase and D-alanine ligase
D-cycloserine
Second line drug with serious side effects: dose related CNS toxicity (headaches, tremors, convulsions, psychosis)
Cycloserine
A 2nd line anti-TB in US, but still a 1st line drug for developing countries (WHO).
-Employed for treatment of life-threatening TB forms (e.g. meningitis) & drugresistant Mycobacteria bacteria
Streptomycin
Does not cross mammalian cell membrane (does not enter CNS or macrophages)
Streptomycin
Amikacin, kanamycin & Capreomycin can be used for strains resistant to
Streptomycin
