Antitubercular antibiotics

The first ever breakthrough in antitubercular chemotherapy took place in the year 1938 with the historical fact that sulphanilamide exhibited week bacteriostatic properties. This observation triggered off the extensive and intensive research towards the synthesis of a number of antitubercular agents which was subsequently followed by certain antitubercular antibiotics. 

Besides, these synthetic compounds discussed above, a number of antitubercular antibiotics have also gained significant recognition over the past few decades. A few typical members of this particular category of compounds are described below ... 

Capreomycin, an antitubercular antibiotic isolated from Streptomyces capreolus A250 in 1960. The cyclopeptide is strongly basic. Four components, designated capreomycin lA (1), IB (2), IIA (3), and IIB (4), have been described as being produced... 

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

Control of tuberculosis, long one of the scourges of mankind, began with the introduction of effective antibacterial agents. Thus, this disease was treated initially with some small measure of success with various sulfa drugs the advent of the antibiotic, streptomycin, provided a major advance in antitubercular therapy, as did the subsequent discovery of isoniazid and its analogs. 

Therapeutic Function Antitubercular Chemical Name Cyclic polypeptide antibiotic Common Name Caprolin Structural Formula ... 

Fig. 5.17 Antitubercular compounds (see text also for details of antibiotics) A, PAS B, isoniazid C, ethionamide D, pyrazinamide E, prothionamide F, thiaeetazone G, ethambutol.

Rifapentine (Priftin) [Antibiotic/Antitubercular Agent] Uses Pulm TB Action X DNA-dependent RNA polymerase. Dose Intensive phase ... 

All mycobacteria produce (3-lactamase. In vitro, several (3-lactamase-resistant antibiotics or a combination of a (3-lactam with (3-lactamase inhibitors, such as clavulanic acid, are active against M tuberculosis and nontubercu-lous mycobacteria. However, the activity of (3-lactam agents against intracellular mycobacteria is generally poor. The (3-lactam agents may be useful in the treatment of MDR tuberculosis in combination with other antitubercular drugs but never as monotherapy. 

The aminoglycoside antibiotic, obtained from Streptomyces griseus is the first antitubercular drug. 

It is used in all forms of tuberculosis along with other antitubercular drugs. Other indications are tularemia, plague, brucellosis, bacterial endocarditis, entero-coccal endocarditis. Used concomitantly with penicillin G for synergistic effect in the treatment of enterococcal endocarditis when other antibiotics are ineffective or contraindicated. 

It is an antibiotic obtained from S. orchidaceus. It is a chemical analogue of D-alanine. It is a second line tuberculostatic antitubercular drug and inhibitor of cell wall synthesis. 

Rifapentine (Priftin) [Antibiotic/Antitubercular Agent1] Uses ... 

Another enzyme-activated inhibitor is the streptomyces antibiotic D-cycloserine (oxamycin), an antitubercular drug that resembles D-alanine in structure. A potent inhibitor of alanine racemase, it also inhibits die non-PLP, ATP-dependent, D-alanyl-D-alanine synthetase which is needed in the biosynthesis of die peptidoglycan of bacterial cell walls. 

Polyketide and non-ribosomal peptides produced by bacteria and fungi often attain the conformations that establish biological activity by cychzation constraints introduced by tailoring enzymes. This includes heterocychzation of cysteines, serines and threonines in non-ribosomal peptides. The second cychzation constraint is macrocychzation in polyketides, such as the above-mentioned antibiotic erythromycin and the antitumor epothilones. Regio- and stereospecific macrocychzation usuaUy occurs at the end of the polyketide and non-ribosomal peptide assembly hnes during chain release by thioesterase domains [49]. However, in the case of antibiotics of the ansamycin class, like the antitubercular drug rifamycin, the final... 

Answer E. For antitubercular activity, isoniazid (INH) must first be metabolically activated via a catalase present in mycobacteria. A decrease in expression of the cat G gene that encodes this enzyme is the mechanism of high-level resistance to INH. Low-level resistance occurs via mutations in the inh A gene that codes for an enzyme involved in synthesis of mycolic acids. Mutations in the gene that codes for DNA-dependent RNA polymerase is an important mechanism of resistance to rifampin and related antibiotics. 

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