Biomimetic antimicrobial polymers: recent advances in molecular design

The increasing prevalence of antibiotic-resistant bacterial infections, coupled with the decline in the number of new antibiotic drug approvals, has created a therapeutic gap that portends an emergent public health crisis. Since the 1980s, host defense peptides (HDPs) have been recognized as antibacterial compounds that do not induce resistance, but are hampered by their high cost and lack of synthetic scalability. Starting in the early 2000s, synthetic (co)polymers have been designed to mimic the salient physiochemical features of HDPs. These polymers have shown broad-spectrum antimicrobial activity, rapid bactericidal kinetics, and a very low propensity to induce resistance. Systematic optimization of the (co)polymer composition, chain length, hydrophobicity, and cationic charge has generated select examples that are also highly biocompatible (non-hemolytic and non-cytotoxic in vitro). These polymers are derived from inexpensive feedstocks and are produced using cost-effective, scalable processes. Accordingly, such polymers may be viewed as early stage pre-clinical candidates for potential use in pharmaceutical or therapeutic applications. In this review, we focus on the key macromolecular design principles that have been gleaned from more than a decade of structure-activity relationship (SAR) studies, as well as some key mechanistic investigations, across this multidisciplinary field. A fundamental understanding of these functional (co)polymers has arisen from a convergence of ideas in polymer chemistry, microbiology, and biophysics. In this context, we emphasize the recent advances from the past few years and emerging opportunities surrounding the rapidly growing field of HDP-mimetic antimicrobial polymers.