Toward Clinical Applications: Transforming Nonantibiotic Antibacterials into Effective Next-Generation Supramolecular Therapeutics

Antibiotic resistance is a major driver of morbidity and mortality worldwide, necessitating alternatives. Due to their mechanism of action, bacteriophages, endolysins, and antimicrobial peptides (coined herein as nonantibiotic antibacterials, NAA) have risen to tackle this problem and led to paradigms in treating antibiotic-resistant bacterial infections. However, their clinical applications remain challenging and have been seriously hampered by cytotoxicity, instability, weak bioactivity, low on-target bioavailability, high pro-inflammatory responses, shorter half-life, and circulatory properties. Hence, to transit preclinical phases and beyond, it has become imperative to radically engineer these alternatives into innovative and revolutionary therapeutics to overcome recalcitrant infections. This perspective highlights the promise of these agents, their limitations, promising designs, nanotechnology, and delivery approaches that can be harnessed to transform these agents. Finally, I provide an outlook on the remaining challenges that need to be tackled for their widespread clinical administration.