Similarly, the flavonoid-induced cell death of cells were also determined using flow cytometry. confirm the membrane and cell wall damages in mycobacterial cells on exposure to flavonoids. Together, these observations could provide impetus for further research in better understanding of anti-tubercular mechanisms of flavonoids and establishing them as lead molecules for TB treatment. is one of the worlds major infectious killer1. More than 50,000 people every week die due to MTB infection and nearly one-third of the global population is asymptomatically infected2. Therefore, in 1993, Tolterodine tartrate (Detrol LA) the WHO promulgated TB as a global health emergency. However, even after a great strive to control TB globally, complete remission is still needed. Combinatorial therapy with anti-TB drugs has long been used as a promising strategy to effectively kill MTB, however, the emergence of drug resistance with drug tolerant strains Tolterodine tartrate (Detrol LA) has become the major hurdle3. Co-infection of TB with HIV4, as well as lack of patient compliance Tolterodine tartrate (Detrol LA) due to lengthy treatment protocol leads to challenges in diagnosis and treatment of TB5. Therefore, the requisite for new antibiotic targets as well as newer drugs are more exigent than ever before to combat antibiotic resistance menace. The microbial cellular machinery mainly targets cell wall synthesis, gene expression and metabolic pathways. Among the limited options of targets, cell wall biosynthesis keeps the utmost widespread clinical utility efficacy for inhibitor designing. Targeting cell wall synthesis makes bacteria prone to rupture by osmotic pressure and therefore, inhibitors targeting cell wall biosynthesis proves to be bactericidal. The significant complex structure of the mycobacterial cell wall with the presence of virulence factors, makes MTB different from the other bacteria. The mycobacterial cell wall comprises of three layers which together form mycolyl-arabinogalactan-peptidoglycan (mAGP) complex. The innermost layer, Peptidoglycan (PG) layer is peculiar to bacterial kingdom and have been well-thought-out as an attractive target for drug designing. Tolterodine tartrate (Detrol LA) Based on the cellular localization of the enzymes, PG layer is synthesized in three distinct stages (I-III)6 and most of the drugs that have been clinically approved act by inhibiting the phase-III of cell wall biosynthesis. Isoniazid and Ethambutol are the only approved drugs which target cell wall biosynthesis by acting on mycolic acid and arabinogalactan layer respectively7C9. With increased bacterial resistance to compounds targeting phase III biosynthesis, phase-I pathway of PG biosynthesis is now contemplated as an alternate target for drug design10. MurI gene encodes for Glutamate racemase enzyme involved in the initial stages of PG biosynthesis and therefore, becomes an attractive target for drug designing. Glutamate racemase involves in the inter-conversion of L- to D-glutamate (DGL), where DGL is a vital constituent of the PG layer formation11,12. In addition, Glutamate racemase (MurI) also has a profound role in sequestering DNA gyrase enzyme. Such proteins with two functions are called Moonlighting proteins. Moreover, accumulated evidence has shown that glutamate racemases are ubiquitous and are fairly conserved across bacterial kingdom. Furthermore, its absence in humans and other eukaryotes13 makes it an attractive target for drug Tolterodine tartrate (Detrol LA) discovery. Since after the discovery of Rifampicin in the year of 1963, the pursuit for new anti- tubercular agents has been Tfpi slow with the last two major drugs licenced several years.
Similarly, the flavonoid-induced cell death of cells were also determined using flow cytometry
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