Uncovering the potentiality of quinazoline derivatives against Pseudomonas aeruginosa with antimicrobial synergy and SAR analysis.

Antimicrobial resistance has emerged as a covert global health crisis, posing a significant threat to humanity. If left unaddressed, it is poised to become the foremost cause of mortality worldwide. Among the multitude of resistant bacterial pathogens, Pseudomonas aeruginosa, a Gram-negative, facultative bacterium, has been responsible for mild to deadly infections. It is now enlisted as a global critical priority pathogen by WHO. Urgent measures are required to combat this formidable pathogen, necessitating the development of novel anti-pseudomonal drugs. To confront this pressing issue, we conducted an extensive screening of 3561 compounds from the ChemDiv library, resulting in the discovery of potent anti-pseudomonal quinazoline derivatives. Among the identified compounds, IDD-8E has emerged as a lead molecule, exhibiting exceptional efficacy against P. aeruginosa while displaying no cytotoxicity. Moreover, IDD-8E demonstrated significant pseudomonal killing, disruption of pseudomonal biofilm and other anti-bacterial properties comparable to a well-known antibiotic rifampicin. Additionally, IDD-8E's synergy with different antibiotics further strengthens its potential as a powerful anti-pseudomonal agent. IDD-8E also exhibited significant antimicrobial efficacy against other ESKAPE pathogens. Moreover, we elucidated the Structure-Activity-Relationship (SAR) of IDD-8E targeting the essential WaaP protein in P. aeruginosa. Altogether, our findings emphasize the promise of IDD-8E as a clinical candidate for novel anti-pseudomonal drugs, offering hope in the battle against antibiotic resistance and its devastating impact on global health.

Virulence factors of Leishmania parasite: Their paramount importance in unraveling novel vaccine candidates and therapeutic targets.

Leishmaniasis is a neglected tropical disease and remains a global concern for healthcare. It is caused by an opportunistic protozoan parasite belonging to the genus Leishmania and affects millions worldwide. This disease is mainly prevalent in tropical and subtropical regions and is associated with a high risk of public morbidity and mortality if left untreated. Transmission of this deadly disease is aggravated by the bite of female sand-fly vectors (Phlebotomus and Lutzomyia). With time, significant advancement in leishmaniasis-related research has been carried out to cope with the disease burden. Still, the Leishmania parasite has also co-evolved with its host and adapted successfully within the host's lethal milieu/environment. Thus, understanding and knowledge of various leishmanial virulence factors responsible for the parasitic infection are essential for exploring drug targets and vaccine candidates. The present review elucidates the importance of virulence factors in pathogenesis and summarizes the major leishmanial virulence molecules contributing to the parasitic infection during host-pathogen interaction. Furthermore, we have also elaborated on the potential contribution of leishmanial virulence proteins in developing vaccine candidates and exploring novel therapeutics against this parasitic disease. We aim to represent a clearer picture of parasite pathogenesis within the human host that can further aid in unraveling new strategies to fight against the deadly infection of leishmaniasis.