Deciphering mechanistic and therapeutic insight of pyrazolopyrimidines into MRSA suppression: comprehensive in vitro...

Antimicrobial resistance (AMR) is a global health crisis that poses an alarming threat, demanding the discovery of new treatment options to combat the AMR armamentarium. The present study involved the exploration of antibacterial scaffolds with their detailed in vitro, mechanistic, and in vivo investigation. The antibacterial susceptibility test performed using the broth microdilution assay revealed four potent scaffolds having diverse chemical architectures. Among the four identified hits, SL-375 emerged as the most potent hit with excellent bactericidal, synergistic, and antibiofilm properties. The mechanistic elucidation through a series of crucial experiments highlighted the potential of SL-375 in initiating the cascade of events elicited by SL-375, which led to cellular dysfunction. Further, an MRSA-infected systemic mice model was developed, which confirmed the in vivo therapeutic efficacy of the potent hit SL-375. Also, the biochemical test performed for safety evaluation revealed the biocompatible nature of SL-375 in the biological system. Additionally, the potent hit SL-375 was found to improve the histo-architecture of lungs and liver, as confirmed through histopathological studies. Moreover, to elaborate our research at the molecular level, an in silico study proposed that the potent hit SL-375 interacts with the DNA gyrase protein of Staphylococcusaureus, providing deeper elucidation into the structural architecture of SL-375. The present study highlights the therapeutic role of potent hit SL-375 in combating the MRSA menace and emphasizes the essentiality of advanced research at the preclinical and molecular levels.