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Learn about the different antimycobacterial agents used in the treatment of tuberculosis and leprosy. Understand the mechanisms of action and classification of these drugs.
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Antimycobacterial Agents • Mycobacteria are a genus of acid-fast bacilli belonging to the Mycobacteriaceae which include the organisms responsible for tuberculosis and leprosy, as well as a number of other less common diseases. • The cell envelope is unique in both structure and complexity and is responsible for mycobacterium pathogenicity or virulence, multiple drug resistance, cell permeability, immunonoreactivity and inhibition of antigen responsiveness, and disease persistence and recrudescence.
Tuberculosis • Tuberculosis is a disease characterized as a chronic bacterial infection caused by Mycobacterium tuberculosis. • The cell wall has a high lipid content resulting in a high degree of hydrophobicity and resistance to alcohol, acids, alkali, and some disinfectants. • It is transmitted via the respiratory route. • The organism appears in water droplets expelled during coughing, sneezing or talking. • TB is a disease which mainly affects the lungs but the organism can spread through the bloodstream and the lymphatic system to the brain, bones, eyes and skin (extrapulmonary tuberculosis; which is much more common in HIV-infected patients).
Tuberculosis • In pulmonary tuberculosis, the bacilli reach the alveoli and are ingested by pulmonary macrophages which secrete substances stimulate surrounding fibroblasts to enclose the infection site leading to formation of granulomas or tubercles.
leprosy (Hansen's disease) • Leprosy (Hansen's disease) is recognized as a chronic granulomatous infection caused by Mycobacterium leprae. The disease may consist of lepromatous leprosy, tuberculoid leprosy, or a condition with characteristics between these two poles referred to as borderline leprosy. • Person-to-person contact appears to be the means by which the disease is spread with entrance into the body occurring through the skin or the mucosa of the upper respiratory tract. • Skin and peripheral nerves are the regions most susceptible to attack where the first signs of the disease consist of hypopigmented or hyperpigmented macules.
leprosy (Hansen's disease) • Neuronal involvement in the extremities will lead to muscle atrophy, resorption of small bones, and spontaneous amputation. • When facial nerves are involved corneal ulceration and blindness may occur. • The identification of the organism in skin or blood samples is not always possible, but the detection of the antibody to the organism is an effective diagnostic test especially for the lepromatous form of the disease.
Mycobacterium Avium-intracellular Complex • Disseminated Mycobacterium avium and Mycobacterium intracellular complex (MAC or MAI) is the most common bacterial opportunistic infection seen in AIDS patients. • The lungs are the organs most commonly involved in non-AIDS patients but the infection may involve bone marrow, lymph nodes, liver and blood in AIDS patients. • MAC grow within macrophages and therefore the drug must be capable of penetration of the macrophage. • Treatment of MAC, both prophylactically and for diagnosed infections requires the use of multiple drug therapy and for disseminated MAC this treatment is for the life of the patient.
General approaches to drug therapy • The pathogenic mycobacterial organism can be divided into organisms that are: • Actively metabolizing and rapidly growing, • Semi dormant in acidic intracellular environment • Semi dormant in a nonacidic intracellular environment, • Dormant. • The dormant being the most problematic and responsible for treatment failures. Thus, successful chemotherapy calls for drugs with bactericidal action against rapidly growing organisms and the ability to destroy semi dormant and dormant populations. • The use of combination therapy over an extended period of time is one answer to successful treatment.
Classification of Anti- TB Drugs: • First–Line Agents: • They are also known as basic or primary agents which are used in the initial treatment. • They are the strongest and most effective agents (lowest toxicity) by which most of TB bacilli are killed, e.g., Isoniazid (INH), Rifampin, Pyrazinamide, Ethambutoland Streptomycin. • Second–Line Agents: • These drugs are utilized in case of resistance, retreatment or intolerance to the first-line agents, e.g. Ethionamide, p-Amino salicylic acid (PAS), Cycloserine.
First-line Agents I.1st Line Agents
1.Isoniazid (Isonicotinic Acid Hydrazide, INH) • INH is a synthetic orally active antibacterial agent with bactericidal action against M. tuberculosis. Mechanism of action • INH is a prodrug which is activated through an oxidation reaction catalyzed by an endogenous enzyme, katG, which exhibits catalase-peroxidase activity converting INH to a reactive species capable of acylation of an enzyme system found exclusively in the M. tuberculosis.
Isoniazid (Isonicotinic Acid Hydrazide, INH) • The reaction of catalase-peroxidase activated INH with a portion of the enzyme inhA (involved in the biosynthesis of the mycolic acids which are important constituents of the mycobacterial cell wall in that they provide a permeability barrier to hydrophilic solutes). • The enzyme inhA is a NADH-dependent enoyl reductase protein involved in double bond reduction during fatty acid elongation.
Isoniazid (Isonicotinic Acid Hydrazide, INH) • INH specifically inhibits long chain fatty acid synthesis, How? • INH is activated to an electrophilic species which acylates the 4- position of the NADH so it is no longer capable of catalyzing the reduction of unsaturated fatty acids essential for the synthesis of the mycolic acids.
Isoniazide (INH): Synthesis
Isoniazid (Isonicotinic Acid Hydrazide, INH) Structure-activity Relationships: • Isoniazid hydrazones possess activity but were unstable in the G.I. tract releasing the active INH i.e. their activity resulted from the INH and not the derivatives. • Substitution of the hydrazine portion of INH with alkyl and aralkyl substituents resulted in a series of active and inactive derivatives.
Isoniazid (Isonicotinic Acid Hydrazide, INH) Structure-activity Relationships: • Substitution on the N2 position resulted in active compounds (R1 = R2 = alkyl; R3 = H), whereas any substitution of the N1 hydrogen with alkyl groups destroyed the activity (R, and R, = H; R3 = alkyl). • None of these changes produced compounds with superior activity over INH.
Isoniazid (Isonicotinic Acid Hydrazide, INH) Metabolism: • INH is extensively metabolized to inactive metabolites. • The major metabolite is N-acetylisoniazid. • The enzyme responsible for acetylation, cytosolic N-acetyltransferase. Individuals possessing high concentrations of the enzyme are referred to as rapid acetylators while those with low concentrations are slow acetylators. This may result in a need to adjust the dosage for fast acetylators. • Acetylhydrazine serve as a substrate for CYP450 resulting in the formation of a reactive intermediate capable of acetylating liver protein resulting in the liver necrosis.
Isoniazid (Isonicotinic Acid Hydrazide, INH) Metabolism • Acetylhydrazine serve as a substrate for CYP450 resulting in the formation of a reactive intermediate capable of acetylating liver protein resulting in the liver necrosis.
2.Rifamycin Antibiotics • The rifamycins are natural products produced by Streptomyces mediterranei. • This chemical class is an aliphatic chain forming a bridge between two nonadjacent positions of an aromatic moiety. • Semisynthetic derivatives are prepared via conversion of the natural rifamycins to 3-formylrifamycin which is derivatized with various hydrazines to give products such as rifampin and rifapentine. • Rifampin and rifapentine have significant benefit over previously investigated rifamycins in that they are orally active, highly effective against a variety of gram-positive and gram-negative organisms, and have high clinical efficacy in the oral treatment of tuberculosis.
Rifamycin Antibiotics Mechanism of Action: • The rifamycins inhibit bacterial DNA-dependent RNA polymerase (DDRP) by binding to the β-subunit of the enzyme leads to a blocking of the initiation of chain formation in RNA synthesis. • Rifamycins are highly active against rapidly dividing intracellular and extracellular bacilli. • Rifampin is active against DDRP from both gram-positive and gram-negative bacteria but due to poor penetration of the cell wall of gram-negative organisms by rifampin, the drug has less value in infections caused by such organisms.
Rifamycin Antibiotics Structure-activity Relationship: • Free OH groups are required at C-l,8,21 and 23 as they are important binding groups for attachment to DDRP. • Acetylation of C-21 and C-23 produces inactive compounds. • Reduction of the double bonds in the macro ring results in a progressive decrease in activity. • Opening of the macro ring gives inactive compounds. These latter two changes greatly affect the conformational structure of the rifamycins which in turn decreases binding to DDRP. • Substitution at C-3 or C-4 results in compounds with varying degrees of antibacterial activity.
Rifamycin Antibiotics Metabolism: • Rifampin and rifapentine are readily absorbed from the intestine although food in the tract may affect absorption. • The major metabolism of rifampin and rifapentine is deacetylation which occurs at the C-25 acetate to give desacetylrifampin and desacetylrifapentine, which are still active antibacterial agents.
Rifamycin Antibiotics Therapeutic Application: • Rifampin (Rifadin, Rimactane) is always used in combination with one or more other antitubercular agents. The drug is potentially hepatotoxic and may produce gastrointestinal disturbances, rash and thrombocytopenic purpura (low levels of platelets that prevents bleeding). • Rifampin is known to induce CYP3A4 and CYP2C isoforms and may decrease the effectiveness of oral contraceptives, corticosteroids, Warfarin, quinidine, methadone, zidovudine, clarithromycin, and the azole antifungal agents.
Rifamycin Antibiotics Therapeutic Application: • Rifapentine is introduced for the treatment of pulmonary tuberculosis and has major advantage over rifampin is the fact that when used in combination therapy rifapentine can be orally administered twice weekly during the "intense" phase of therapy followed by once a week during the "continuous" phase of therapy. • In contrast, rifampin is normally administered daily during the "intense" phase of therapy followed by twice a week dosing during the "continuous" phase of therapy.
3.Pyrazinamide • Pyrazinamide (PZA, pyrazinecarboxamide) is a bioisostere of nicotinamide and possess bactericidal action against M. tuberculosis . • It is a heterocyclic amide derivative.
Pyrazinamide Mechanism of Action • Pyrazinamide may be active totally or in part as a prodrug. • Pyrazinoic acid may lower the pH in the immediate surroundings of the M. tuberculosis to an extent that the organism is unable to grow. • The obvious structural similarity between pyrazinoic acid and nicotinamide would suggest that the pyrazinoic acid might function as an antimetabolite of nicotinamide and interfere with the synthesis of NAD.
MOA • PZA diffuses into the mycobacterium by positive diffusion, then it is converted into POA by the pyrazineamidase enzyme accumulation of POA inside the cell pH of the surroundings of the M. tuberculosis that the organism is unable to grow. • Resistant strains of TB do not produce pyrazinamidase enzyme. Synthesis
Pyrazinamide Structure-activity Relationship • Substitution on the pyrazine ring or the use of alternate heterocyclic aromatic rings have given compounds with reduced activity. • Using QSAR a series of analogs have been prepared with improved biologic activity. The requirements for successful analogs include: • Provision for hydrophilicity to allow sufficient plasma concentrations such that the drug can be delivered to the site of infection. • Lipophilicity to allow penetration into the mycobacterial cell. • Susceptibility to hydrolysis such that the prodrug is unaffected by the "extracellular" enzymes but is readily hydrolyzed at the site of action.
Pyrazinamide Structure-activity Relationship • Examples; 5-chloropyrazinamide and 2-(2'-methyldecyl)-5-chloropyrazinamide
Pyrazinamide Metabolism
Pyrazinamide Therapeutic Application • Pyrazinamide is an essential component of combination therapy for the oral treatment of tuberculosis (component of Rifater with INH and Rifampin) as it is especially beneficial in that it is active against semi-dormant intracellular tubercle bacilli that are not affected by other drugs and reduced treatment regimens to 6 months from the previous 9 month therapy. • The major serious side effect of pyrazinamide is the potential for hepatotoxicity.
4.Ethambutol (Myambutol) • Ethambutol, an ethylenediiminobutanol, (EMB) is administered as its (+)-enantiomer which is 200-500 times more active as a bacteriostatic agent than its (-) enantiomer.
Ethambutol (Myambutol) Mechanism of Action • EMB inhibits the synthesis of the AG portion of the cell wall (inhibits the transfer of mycolic acid into bacterial cell wall). • EMB inhibits the enzymes arabinosyl transferases which catalyze the polymerization of D-arabinofuranose leading to the unique outer envelope [which consists of arabinofuranose and galactose] AG. Thus EMB blocks both the synthesis of AG and LAM of the cell wall. • This mechanism of action accounts for the synergism seen between EMB and intracellular drugs such as rifampin; Damage to the cell wall created by EMB improves the cell penetration of the intracellular drugs resulting in increased biological activity.
Ethambutol (Myambutol) Structure-activity Relationship • Extension of the ethylene diamine chain. • Replacement of either nitrogen. • Increasing the size of the nitrogen substituents. • Moving the location of the alcohol groups. • All are changes that drastically reduce or destroy biologic activity.
Ethambutol (Myambutol) Metabolism • The majority of the orally administered ethambutol is excreted unchanged (73%), with no more than 15% appearing in the urine as either Metabolite A, or Metabolite B (inactive)
5.Streptomycin • Streptomycin (STM) was isolated from a manure-containing soil sample and was ultimately shown to be produced by Streptomycesgrisueus. • The hydrophilic nature of STM results in its very poor absorption from the gastrointestinal tract and therefore STM is commonly administered IM.
Streptomycin Mechanism of Action • STM inhibits protein synthesis, but additional effects on misreading of a m-RNA template and membrane damage may contribute to the bactericidal action of STM.
Streptomycin Structure-activity Relationship • Reduction of the aldehyde to the alcohol results in a compound, dihydrostreptomycin, which has activity similar to STM but with a greater potential for producing delayed severe deafness (major side effect). • Oxidation of the aldehyde to a carboxyl group or conversion to Schiff’s base derivatives (oxime, semicarbazone, or phenylhydrazone) results in inactive analogs. • Oxidation of the methyl group in α-streptose to a methylene hydroxy gives an active analog but with no advantage over STM.
Streptomycin Structure-activity Relationship • Modification of the aminomethyl group in the glucosamine portion of the molecule by demethylation or by replacement with larger alkyl groups reduces activity. • Removal or modification of either guanidine in the streptidine nucleus results in decreased activity.
Streptomycin • Metabolism
II- Second-Line Agents • While these agents are active antibacterial agents, they usually are less well tolerated or have a higher incidence of adverse effects. • These agents are utilized in cases of resistance, retreatment or intolerance to the first-line drugs.
