Treatment for Anti-mycobacterial drugs includes:
Rifampin, Isoniazid, Pyrazinamide, Ethambutol for 2 months
Then, Isoniazid and Rifampin for another 4 months
Mycobacteria have a very unique __________________
Are ________ Bacilli, are ________ growing.
Is Gram _____ (Sort of)
Cell envelop
Acid fast
Also slow growing
Positive
Mycobacteria have ___________
Mycolic Acids (C60-90)
Isoniazid is a _____________
pro-drug
Isoniazid is activated by _____________
KatG
The chemical intermediates that are activated by the Isoniazid prodrug chemically react with?
NADH cofactor
How do Isoniazid chemical intermediates react with NADH?
They react with C4 on the nicotinamide ring of the NADH cofactor
This adduct inhibits enoyl reductase
Blocking Enoyl Reductase prevents what?
Synthesis of Mycolic Acid
Why is the acetylation of Isoniazid via metabolism of great concern?
Acetylhydrazide is produced with is hepatotoxic (Acetylates liver proteins)
Rifampin MOA?
Napthalene ring interacts with what?
Inhibits bacterial RNA Polymerase.
aromatic amino acids in polymerase via pi-pi interactions
Aliphatic OH groups H-bond to _______________
Phenolic OH groups bind ______________
amino acids in polymerase
zinc in the polymerase
Primary Rifampin metabolite is _____________; still some _________
Rifampin is acid catylzed, so there is a loss of the _____________ Ring
deacetylated
activity
Piperazine
Rifapentine (Priftin) is much like Rifampin, but has a __________ added to the Piperazine
Cyclopentane
Pyrazinamide is a _________________ of nicotinamide
Bioisostere
MOA of Pyrazinamide?
Not known
Pyrazinamide is a ____________. Active form is ____________
Prodrug
pyrazinoic acid
Pyrazinamide lowers _________, which may contribute to the killing of mycobacterium.
Resistance occurs through mutation of ________
pncA (pyrazinadmidase)
Ethambutol MOA?
Disrupts synthesis of the arabinose and galactose region of the cell wall
Thought to mimic arabinose sugar, and blocks production of AG
Ethambutol weakens ___________; intracellular drugs can then get in (Rif)
cell wall
Streptomycin is one of the few aminoglycosides that can ____________.
Inhibits __________.
Metabolized by_______________________
penetrate the M. tb cell wall
protein synthesis
adding a phosphate or adenylate group to sugar -OH
Ethionamide (2nd line) inhibits _______________.
enoyl reductase
Cycloserine (2nd line) is an analog of _________. Blocks ______ linkage
D-Ala
Blocks D-Ala linkage
Fluoroquinolones work on a wide range of ____________ and _________ bacteria
Inhibits?
Gram +, Gram -
DNA Gyrase
Only _________ form of fluoroquinolones active against mycobacteria. Best ______ substituent for mycobacteria
fluorinated
C7
MAC (Mycobacterium avium-interacellulare complex) Treatment includes what?
_________ and _________ are ineffective
Ethambutol + Ciprofloxacin work well
INH, pyrazinamide
_____________ has been used since 1943 to treat leprosy
Dapsone
___________ are the major class that treats Leprosy
How do they work?
Diaryl sulfones
Blocks synthesis of folic acid
Sulfonamides are bacter_____. They inhibit _____________, competes w/___________ to block folate production.
static
dihydropteroate synthase
p-aminobenzoic acid
No folate means no __________ => No _____________
thymidine
DNA synthesis
sulfadiazine has a ___________. Used topically for __________.
Negatively charged Nitrogen in the Sulfonamide group which is stabilized by resonance.
Burns
Sulfisoxazole is a _________. Used in pediatric patients because?
Often used in combination with___________________
Prodrug
tasteless
Erythromycin
Sulfamethoxazole is used in combo with __________
Trimethoprim
Why is SMZ used with TMP?
The likelihood of a bacterium conferring resistance against both is very rare. Usually has to happen in two steps.
What is the latest TB drug to be created?
First drug to specifically target _________________
Sirturo (bedaquilin)
MDR M. tb
Sirturo has a black box warning considering?
Cardiovascular risk (arrhythmia possible)