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

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

  • J Antibiot (Tokyo). 2024 Mar 21. doi: 10.1038/s41429-024-00717-3.
Rakshit Manhas 1 Arti Rathore 1 2 Ujwal Havelikar 1 Shavi Mahajan 1 Sumit G Gandhi 1 2 Avisek Mahapa 3 4
Affiliations

Affiliations

  • 1 Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India.
  • 2 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 3 Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India. avisek.mahapa@iiim.res.in.
  • 4 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. avisek.mahapa@iiim.res.in.
Abstract

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.

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