Hydrophilic Phage-Mimicking Membrane Active Antimicrobials Reveal Nanostructured-Dependent Activity and Selectivity

Speaker

Hongjun Liang, Texas Tech

Abstract

Antimicrobial (host-defense) peptides (AMPs) and synthetic mimics of AMPs (SMAMPs) are widely considered as promising candidates of the next generation antibiotics that can fight tough bacteria infections and thwart bacterial resistance. Cationic charge and amphiphilicity have been identified as the two key antibiotic traits that help those membrane active antimicrobials disrupt bacteria membranes. Because this mode of damage works nonspecifically through synergistic hydrophobic and charge interactions, the possibility to induce resistant bacterial strains is greatly reduced. Nevertheless, direct use of AMPs is hindered by their expense, toxicity, and limited tissue distribution, and the development of SMAMPs faces a central dichotomy: the hydrophobicity believed to be critical for their antimicrobial activity also causes toxicity to mammalian cells. Numerous chemical variations have been tested in search of a delicate, yet unquantifiable balance, between amphiphilicity and electropositivity. I will discuss here a different approach to develop membrane active antimicrobials by designing well-defined polymer molecular brushes (PMBs) that mimic the basic structural motifs of bacteriophages. Phages use proteinaceous devices first and foremost recognized by their unique nanostructures to attack bacteria selectively and gain entrance or egress. We do not intend to replicate the receptor-based specific viral binding to bacteria. Rather, we aim to mimic the nanoscale viral structural features that give rise to their unique multivalent interactions on remodeling bacterial membranes. Our preliminary data show that: (1) amphiphilicity is not a required trait – hydrophilic PMBs can be potent antimicrobials with negligible hemolytic activity; (2) PMBs are far more powerful antibiotics than individual linear-chain polymers that make up the PMBs; (3) the nanostructured PMBs induce a topological change of bacteria membranes to form pores, while their individual linear chain polymer branches do not; and (4) the size and shape of PMBs help define their activity and selectivity. These findings expand existing wisdom on the design of membrane active antimicrobials and suggest that nanostructure is another determinant that can be judiciously controlled to offer synergistic multivalent interactions on remodeling bacterial membranes.