Promising antimicrobial agents designed from natural peptide templates

Treatment of infectious diseases is a paramount healthcare issue as the number of multidrug resistant pathogens rise rendering our aging small-molecule antibiotics ineffective. Innovation and discovery in new molecular species that are active against novel targets is vital to meet the challenges of resistance development. The ability of host-defense, or antimicrobial, peptides (AMPs) to selectively target the harmful microbial membrane over that of a host’s is a unique characteristic making these innate immune effectors promising candidates to fill the growing therapeutic void. Despite nearly two decades of active research into their selective mechanism against pathogens, few peptides have been found suitable for pharmaceutical applications. Fundamental structure–activity principles underlying the physiochemical properties of AMPs have guided the development and design of synthetic alternatives to peptide-based drugs. Here we first review work in understanding the mechanism and membrane selectivity of AMPs as it provides a good basis for the interpretation of other membrane-active agents as the same physical and chemical driving forces are at work. Recent advances in the rational design of synthetic mimics of antimicrobial peptides (SMAMPs) will also be discussed. Emphasis is placed on the paradigm shift that a rigid secondary structure is not required for the membrane-disruptive ability of SMAMPs.