Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids

Abstract

AbstractTuberculosis (TB) is caused by Mycobacterium tuberculosis (MTB), a highly infectious disease accounting for nearly 1.5 million deaths every year and has been a major global concern. Moreover, resistance to anti-TB drugs is an arduous obstacle to effective prevention, TB care and management. Therefore, incessant attempts are being made to identify novel drug targets and newer anti-tubercular drugs to fight with this deadly pathogen. Increasing resistance, adverse effects and costly treatment by conventional therapeutic agents have been inclining the researchers to search for an alternative source of medicine. In this regard natural compounds have been exploited extensively for their therapeutic interventions targeting cellular machinery of MTB. Glutamate racemase (MurI) is an enzyme involved in peptidoglycan (PG) biosynthesis and has become an attractive target due to its moonlighting property. We screened various classes of natural compounds using computational approach for their binding to MTB-MurI. Shortlisted best docked compounds were evaluated for their functional, structural and anti-mycobacterial activity. The results showed that two flavonoids (naringenin and quercetin) exhibited best binding affinity with MTB-MurI and inhibited the racemization activity with induced structural perturbation. In addition, fluorescence and electron microscopy were employed to 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.