Use Of Mycobacterium Tuberculosis Lipolytic Enzymes For Treatment

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A strategy for disease prevention and the spread of resistant strains is targeting different parts of the bacteria. For example, targeting the membrane of mycobacterium can be a chemotherapy intervention and a good way to slow down the progression of genetic resistance and kill drug-resistant basil and eventually shorten the duration of anti-TB regimens. While the synthesis of arabinogalactan and mycolic acid is still a primary target for available drugs, the mechanisms for the transfer and synthesis of peptidoglycan and decaprenyl-phosphate carrier lipids can also be used as a substantial target.

Likewise, the mycobacterial membrane protein large (MMPL), which plays a vital role in the transmission of lipid in the pathogen, can be an attractive drug target. Because the growth of mutants with defects in type 2, 4, 5, 7, 8, 10 and 11 of these proteins significantly reduce the rate of infection in the mice lungs. Also, the combination of SQ109 as an inhibitor of type 3 of this protein synergistically with anti-tuberculosis drugs shortens the treatment period. Additionally, indole carboxamides, adamantyl urease, tetrahydropyrazolopyrimidine and also diarylpyrrole BM212 can inhibit transmission of MmpL3, probably due to their ability to eliminate the transmembrane electrochemical proton gradient.

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Efflux mechanisms may also be inhibited by some of the compounds of thioridazine, which have high capacity for efflux inhibition as well as low toxicity and significant synergistic effects with anti-TB drugs both in vitro and in macrophages. Therefore, these compounds can be used as an auxiliary drug for the treatment of tuberculosis. It has been shown that AZD5847, as a new anti-TB agent, has a good effect against Mycobacterium tuberculosis by inhibiting protein synthesis and using it during the primary bactericidal phase and sterilization stage of treatment can be beneficial. Mtb has certain enzymatic activities that various compounds can affect the growth and survival of the bacteria and inhibit these enzymes; for example, the antigen 85 of this bacterium has a mycolyl transferase activity and thus can be used as a target for controlling DR-TB.

On the other hand, short single stranded DNA as a new class of potent inhibitors of acetohydroxyacid synthase (AHAS) can be a new drug candidate against drug-resistant tuberculosis. Also, the increased matrix metalloproteinases (MMPs) in tuberculosis can cause cell recruitment, tissue destruction, cavitation and release of matrix degradation products which is related to the severity of disease. However, its secretion can be controlled by signaling pathways and transcription factors of various immune cells and is considered as an interesting drug target. N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) can also be used as a significant target for the development of anti-TB drugs.

Also, Shikimate kinase (SK) is an essential enzyme for the survival of bacteria. However, the combination 5631296 as an inhibitor of this enzyme has a mycobactericidal activity in synergy with rifampicin. In addition, isocitrate lyase (ICL) and methionine aminopeptidase (METAP) is essential mycobacterial enzymes in maintaining the latency of TB infection, which salicylanilide derivatives are important as inhibitors of these two enzymes. For example, salicylanilide pyrazinoates, as antimycobacterial agents, can inhibit Mtb resistant strains. Also, APS reductase (APSR) plays a role in biosynthesis of essential sulfur molecules for the survival and pathogenesis of bacteria. Thus, the inhibitors of this enzyme can significantly affect the level of cellular sulphurous metabolites in alive mycobacterium.

The Histone deacetylase 6 (HDAC6) enzyme that inhibits IL-10 is inhibited by Tubastatin A and further strengthens the immune response and restricts the growth of mycobacterium. Inhibition of the bacterial I-asparaginase enzyme, which plays the role in nitrogen assimilation and neutralization of acidic condition within alveolar macrophages, can be effective against infection. Mycobacterial caseinolytic protease enzymes P1 and P2 can also be controlled by bortezomib (Velcade), an effective anti-tuberculosis agent that has bactericidal properties. Also, Phosphopantetheine adenylyltransferase (CoaD) and dephospho CoA kinase (CoaE) enzymes are necessary for bacterial survival. Therefore targeting of these enzymes can be suitable for the development of inhibitors against this bacterium. Propargyl-linked antifolates also act as potent inhibitors of the dihydrofolate reductase (DHFR) of Mtb that penetrate into the outer membrane.

As can be seen, the various enzymes of Mtb can be changed by various compounds and drugs, and by preventing their activity, they affect the function and life of the bacterium, and thus they are used in the treatment and prevention of the disease and the prevalence of drug-resistant strains.

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