Next-Generation Antimicrobial Peptides: Mechanistic Insights and Delivery Strategies against ESKAPE Pathogens

The present global health concerns of deaths of patients with diseases caused by Multidrug-Resistant (MDR) bacterial pathogens like P. aeruginosa and S. aureus result in 1.27 million deaths annually and could lead to an estimated 10 million annual deaths in 2050,which is higher than number of deaths due to cancer, if no action is taken. This situation is the emergence of resistant genes from industrial effluents, residential waste, and hospital management waste, and the evolution of a new immune response in bacteria. Traditional antibiotics in the face of a failure approach in combating MDR bacteria. Some of the most threatening bacterial strains identified by the WHO, known as the ESKAPE pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus, use their survival mechanisms to counteract conventional drug treatments. The aim of this review is to highlight these Host Defense Peptides (HDPs) which target the electrostatic charge of the outer membrane and the lipid bilayer, creating a multifaceted assault through the dissipation of the proton motive force (PMF) and the induction of reactive oxygen species (ROS). Through the transition from simple extraction to the construction of high-fidelity databases and the use of machine learning architectures like dsAMPGAN and HydrAMP, researchers can now optimize synthetic-natural peptides for minimal hemolytic effect on human red blood cells. Exploration of the synergistic approach with animal derived peptides with traditional -lactam antibiotics , to help traditional antibiotics reach their targets, alongside the integration of advanced delivery systems such as gold nanoparticles (AuNPs) using plant-derived antimicrobial peptides nanoemulsions to solve problems associated with proteolytic resistance. New applications of the plant-derived antimicrobial peptides in environmental and agricultural biotechnology sectors other than pharmaceutical biotechnology.