Harnessing biological insights to accelerate drug discovery against ESKAPE pathogens

The escalating global health crisis of antimicrobial resistance (AMR) is driven by the increasing prevalence of drug-resistant bacterial infections, particularly among ESKAPE pathogens. These multidrug-resistant bacteria pose a significant threat to public health, causing severe and fatal infections in healthcare settings. To combat AMR, a comprehensive understanding of the mechanisms of drug resistance employed by ESKAPE pathogens is crucial. These bacteria utilize various strategies, including drug inactivation, modification, and overexpression of antibiotic target sites, efflux pump overexpression, and porin protein reduction, to evade the effects of antibiotics. Addressing this urgent challenge requires a concerted effort to develop novel antimicrobial agents. Our review highlights the promising drug targets that can be exploited for therapeutic interventions. A preclinical roadmap is outlined, emphasizing the essentiality of various antibacterial susceptibility assays and studies to identify potent drug candidates. Furthermore, to broadly explore the associated pathogenesis, virulence, host immune responses, and therapeutics, various in vitro and in vivo infection models have been explored that pave the way for unraveling novel therapies against a wide spectrum of ESKAPE pathogens. Lastly, this review delves into the significant challenges faced by the research community in the drug discovery process and explores potential avenues to combat the growing threat of drug-resistant pathogens.