Polypept(o)ide-based bactericides: weapons against antibiotic-resistant bacterial infections

Emerging antibiotic resistance in bacterial pathogens has necessitated the development of alternative ‘outside of the box’ antimicrobial therapeutics. Polypept(o)ide-based bactericides with chemical structures mimicking antimicrobial host defense peptides have emerged as promising candidates for treating antibiotic-resistant and recurring infections. This review summarizes the recent advances in membrane-active polypept(o)ide-based bactericides in the treatment of antibiotic-resistant bacterial infections associated with the physical disruption of bacterial cell walls/cell membranes. Among these polypept(o)ide-based bactericides, nonantibiotic treatment strategies are employed to combat lethal bacterial strains resulting from acquired antibiotic resistance and biofilm formation, featuring the capacity to evade acquired antibiotic resistance-related mechanisms and to alleviate the emergence of drug resistance. Emphasis will focus on the typical polypept(o)ides with diverse molecular conformations (e.g., linear, brush-like, and star-shaped) and various chemical structures of monomers (e.g., α-amino acid, β-amino acid, and N-substituted glycine) that are central to the performance of antimicrobial polypept(o)ides. Finally, a brief discussion of the key challenges and prospects of polypept(o)ide-based bactericides is presented.