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PHRM 304
Mycobacterium tuberculosis
Main etiological agent of tuberculosis (TB) 2nd leading infectious cause of death after HIV Can remain dormant for years Most host never develop the disease In 2007, 353,000 TB patient were found In Bangladesh (6th in the world, WHO)
Mycobacterium tuberculosis
Antitubercular drugs
Combined treatment of two or more drugs is used. Advantages: Prevents emergence of resistance Additive effect: smaller dose is sufficient
First-line agents
Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin
Second-line agents
Ethionamide, p-aminosalicylic acid, cycloserine, capreomycin, and kanamycin Active antibacterial agents, but they usually are less well tolerated or have a higher incidence of adverse effects Utilized in cases of resistance, retreatment, or intolerance to the first-line drugs
First-line agent
Hydrazide
N-N covalent bond Four substituents One acyl group
Hydrazide
Isoniazid (INH)
Isoniazid (INH)
Isoniazid (INH) is a synthetic antibacterial agent Considered to be the primary drug for treatment
Mechanism of action
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG. Inhibiting the synthesis of mycolic acids, important constituents of the mycobacterial cell wall Most active drug for tuberculosis
Mechanism of action
In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellularly.
O C OH
Active compounds (R1 and/or R2 = alkyl ; R3 = H) Destroyed the activity (R1 and R2 = H/alkyl; R3 = alkyl)
Hydroxamic acid
Amide
Iproniazid
Tuberculostatic Psychostimulant Hepatotoxic: no longer used
Hydrazone
Isoniazid hydrazone Synthesis: INH react with aldehyde and ketone Prodrug: Similar activity Activate in GI tract
Second-line agent
P-AMINOSALICYLIC ACID
p-aminosalicylic acid
p-aminosalicylic acid
It was the second antibiotic found to be effective in the treatment of tuberculosis, after streptomycin. PAS is always used in combination with other anti-TB drugs.
p-aminosalicylic acid
Its potency is less than that of the current five first-line drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin) for treating tuberculosis, but it is still useful in the treatment of multidrug-resistant (MDR) tuberculosis.
-NH2 -OH
Mechanism of action
The mechanism of action is very similar to that of sulfonamides, which inhibit dihydropteroate synthase and thus the biosynthesis of folic acid. Structurally similar to PABA & sulfonamides.