Infections caused by a variety of microorganisms, including bacteria, viruses and fungi are of increasing global concern, and polymicrobial diseases caused by combinations of microorganisms are recognized with increasing frequency. Yet the clinical pipeline of new antimicrobials is dry, with only 6 innovative antibiotics that address the WHO list of priority pathogens in development in 2019. Antimicrobial peptides (AMPs) with broad-spectrum activity represent a novel source of potential antimicrobials. Yet the clinical development of AMPs as antimicrobial drugs is hampered by a number of factors, especially their enzymatically labile structure. We report here the astonishingly broad-spectrum antimicrobial potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers), across three different classes of infectious organisms. Peptoids are insensitive to proteases and thus are better drugs than peptides. Our results demonstrate that several peptoids exhibit potent in vitro and in vivo activity against all of the ESKAPE bacterial pathogens, the very resilient M. tuberculosis bacteria, Influenza, HSV-1, and SARS-CoV-2 virus and a range of fungi, making them good drug candidates for treating polymicrobial infections.
We find that some of these peptoids permeabilize membranes even faster than natural AMPs, and act by direct non-specific physical aggregation of intracellular macro-anions, including ribosomes and DNA, resulting in a rapid rigidification of the bacterial cytoplasm. We discuss how and why differing molecular features between different peptoid candidates affects antimicrobial activity and selectivity, specifically, the self-assembly of the most effective peptoids into discrete micellar structures such as ellipsoidal micelles comprising ~100 peptoid molecules per micelle, or helical bundles comprising 2-4 peptoid molecules per bundle. We confirm that these peptoids exhibit no apparent cytotoxicity in vitro with primary human cells at concentrations of up to 256 µg/mL and are well tolerated in vivo, making them exciting drug candidates as a novel class of broad-spectrum anti-infectives.