Bactericidal activity of esculetin is associated with impaired cell wall synthesis by targeting glutamate racemase of Neisseria gonorrhoeae.

ABSTRACT

Neisseria gonorrhoeae (NG), the causative organism of gonorrhea, has been classified by the World Health Organization as 'Priority' two organism owing to its increased resistance to antibiotics and even failure of recommended dual therapy with ceftriaxone and azithromycin. As a result, the general and reproductive health of infected individuals is severely compromised. The imminent public health catastrophe of antimicrobial-resistant gonococci cannot be understated, as t he of severe complications and sequelae of infection are not only increasing but their treatment has also become more expensive. Tenacious attempts are underway to discover novel drug targets as well as new drugs to fight against NG. Therefore, a considerable number of phytochemicals have been tested for their remedial intercession via targeting bacterial proteins. The MurI gene encodes for an enzyme called glutamate racemase (MurI) that is primarily involved in peptidoglycan (PG) biosynthesis and is specific to the bacterial kingdom and hence can be exploited as a potential drug target for the treatment of bacterial diseases. Accordingly, diverse families of phytochemicals were screened in silico for their binding affinity with N. Gonorrhoeae MurI (NG-MurI) protein. Esculetin, one of the shortlisted compounds, was evaluated for its functional, structural, and anti-bacterial activity. Treatment with esculetin resulted in growth inhibition, cell wall damage, and altered permeability as revealed by fluorescence and electron microscopy. Furthermore, esculetin inhibited the racemization activity of recombinant, purified NG-MurI protein, one of the enzymes required for peptidoglycan biosynthesis. Our results suggest that esculetin could be further explored as a lead compound for developing new drug molecules against multidrug-resistant strains.