Metabolism of mycobacteria

Metabolism of Mycobacteria It has been established that the biochemical constitution of mycobacteria is of rather complex nature. The meticulous meaningful researches have discovered certain novel chemical structures, but the ensuing relationship between these and the pathogenic and biologic activities of mycobacteria yet remain to be elucidated and expatiated satisfactorily. Though copious volume of informations with respect to the precise metabolism of mycobacteria are available however, the exhaustive overall picture of the mycobacterial metabolism is far from plausible acceptable completion. 

Mecfianism of Action An isonicotinic acid derivative that interferes with RNA synthesis. Therapeutic Effect Suppresses the multiplication of mycobacteria. Pharmacokinetics Rapidly and well absorbed from the G1 tract. Protein binding 20%-30%. Widely distributed. Metabolized in the liver. Primarily excreted in urine. Removed by hemodialysis. Half-life 3-4 hr (increased in impaired renal function). 

The most detailed investigations into PolyP metabolism of the Mycobacteria and Corynebacteria have been carried out by Drews (1960a,b), Mudd and co-workers (Mudd... 

Possible pathways of PolyP metabolism in Mycobacteria (Szymona, 1964). 

Clarithromycin and azithromycin are used to treat MAC and other nontuberculous mycobacteria. Clarithromycin alters the metabolism of many other drugs that are metabolized by CYPs, leading to many potential drug interactions. The broader pharmacology of these macrohdes is presented in Chapter 46. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

Recently V-containing analogues of rhamnose have been proposed for treating diseases such as leprosy and tuberculosis caused by mycobacteria which contain rhamnose in the cell wall since rhamnose has no role in mammalian metabolism. Design and synthesis of specific inhibitors of ihamnosidase have been reported [136,137],... 

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. 

Michael S. Scherman received his B.S. (Microbiology) and his M.S.B.A (Computer Information Systems) from Colorado State University, CO, USA. He has worked with Dr. Michael R. McNeil at the Mycobacteria Research Laboratories at Colorado State University since 1992, studying the structural aspects of the mycobacterial cell envelope, TB drug development, targeting of key biosynthetic enzymes, and computer modeling of metabolic and enzymatic pathways and structures. 

Why isoniazid causes this type of anemia is not well understood but it is well established that the toxic effects of long-term isoniazid therapy of tuberculosis can be significantly diminished by coadministration of Vitamin B6. This is somewhat surprising since the primary anti-TB mechanism of action for isoniazid appears to be the inhibition of mycolic acid, an important substituent in Mycobacteria cell walls, which is not Vitamin B6 dependent. However, Vitamin B6 does play an important role in heme synthesis. Since the administration of Vitamin B6 with isoniazid can reverse the formation of sideroblastic anemia it seems likely that isoniazid affects Vitamin B6 in a number of important metabolic pathways. 

A major fate of PA is conversion to DG that can be metabolized to PC, PE, and TG (Fig. 1). Alternatively, PA can react with CTP to form CDP-DG that is utilized for biosynthesis of the inositol phospholipids as well as phosphatidylglycerol (PG) and diphosphatidylglycerol (DPG) (Fig. 1). Inositol is a cyclohexane derivative in which all six carbons contain hydroxyl groups. The most common inositol isoform is myo-inositol but other less abundant inositols with different structures also occur. The first report of an inositol-containing lipid was in 1930 in Mycobacteria which is ironic since inositol lipids are rarely found in bacteria. Brain is the richest source of inositol-containing lipids, as first discovered by Folch and Wooley in 1942. In 1949, Folch described a PI phosphate (PI-P) that was later found to include PI and PI bisphosphate (PI-P2). The chemical structures of PI, PI-P, and PI-P2 were determined by Ballou and co-workers between 1959 and 1961. PI (1.7 pmol/g liver) constitutes -10% of the phospholipids in cells and tissues. PI-P and PI-P2 are present at much lower concentrations (1-3% of PI). In 1958, Agranoff and co-workers first reported the incorporation of [ HJinositol into PI. Subsequently, Paulus and Kennedy showed that CTP was the preferred nucleotide donor. 

Table 13.1 shows a list of some bacteria with the number of CYPs associated with their genomes to date. Most striking are the number and diversity seen among actinomycetes such as strep-tomycetes and mycobacteria, although some actinomycetes, such as Corynebacterium diptheriae, have no CYPs. Much of the CYP diversity is likely to be due to their role in secondary metabolism, as is true in the filamentous gram-negative... 

The emergence of further streptomycete genomes will add to our understanding of CYP evolution, and the numbers of CYPs in unknown pathways of secondary metabolism will reveal new natural products. Given the estimate that only 1% of microorganisms are culturable, the depth of the biocatalytic reservoir of CYPs becomes evident. The reason why the streptomycetes and mycobacteria have many CYPs is not clear, as other soil bacteria contain either small numbers of CYPs (Table 13.1) or none. 

Nebularine was originally isolated from the mushroom Agaricus (Clito-cybe) nebularis but it has been detected as a metabolic product of a streptomycete it has a strong inhibitory action on cell growth and on mycobacteria. The structure has been shown by degradation (and confirmed by synthesis ) to be that of 9-/3-D-ribofuranosylpurine (28). 

Mechanisms The mechanism of action of pyrazinamide is not known however, its bacteriostatic action appears to require metabolic conversion via pyrazinamidases (encoded by the pncA gene) present in M tuberculosis. Resistant mycobacteria lack these enzymes, and resistance develops rapidly if the drug is used alone. There is minimal cross-resistance with other antimycobacterial drugs. 

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