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

Abstract

The prevalent wisdom on developing membrane active antimicrobials (MAAs) is to seek a delicate, yet unquantified, cationic-hydrophobic balance. Inspired by phages that use nanostructured protein devices to invade bacteria efficiently and selectively, we study here the antibiotic role of nanostructures by designing spherical and rod-like polymer molecular brushes (PMBs) that mimic the two basic structural motifs of bacteriophages. Three model PMBs with different well-defined geometries consisting of multiple, identical copies of densely packed poly(4-vinyl-N-methylpyridine iodide) branches are synthesized by controlled/"living" polymerization, reminiscent of the viral structural motifs comprised of multiple copies of protein subunits. We show that, while the individual linear-chain polymer branch that makes up the PMBs is hydrophilic and a weak antimicrobial, amphiphilicity is not a required antibiotic trait once nanostructures come into play. The nanostructured PMBs induce an unusual topological transition of bacterial but not mammalian membranes to form pores. The sizes and shapes of the nanostructures further help define the antibiotic activity and selectivity of the PMBs against different families of bacteria. This study highlights the importance of nanostructures in the design of MAAs with high activity, low toxicity, and target specificity.

Biomimetic antimicrobial polymers: recent advances in molecular design

“…Antibacterial nanostructures composed of spherical and rod-shaped graft copolymers that display quaternized poly(vinyl pyridine)s showed a strong dependence of activity on chain architecture. 94 Interestingly, the smaller spherical-shaped nanostructures exhibited stronger antibacterial activity as compared to rod-like graft copolymers and linear polymer chains.…”

Antimicrobial and Osseointegration Properties of Nanostructured Titanium Orthopaedic Implants

“…Mimicking the two basic structural motifs of bacteriophages, spherical and rod-like polymer molecular brushes (PMBs) have been designed. However, the impact of these techniques for Ti implants is unclear in future [ 182 , 183 ]. However, for the practical performances the two-dimensional surface structures such as nano-grits, nano-tube, or nano-ripple are critical ( Figure 4 and Table 4 ).…”

Peptides With Triplet-Tryptophan-Pivot Promoted Pathogenic Bacteria Membrane Defects

“…Antimicrobial peptides, which are regarded as the antibiotic substitute with the most potential for being not affected by traditional mechanisms of bacterial resistance, lead to cell death by physical disruption of the pathogen's membrane and subsequent leakage of cytoplasmic components, which greatly reduces the development of resistance against drugs (Makovitzki et al, 2008;Wimley, 2010;Teixeira et al, 2012;Jiang et al, 2017). Thus, the antibacterial mechanisms of S5 and S7 were further confirmed by testing the interaction of peptides with lipopolysaccharide (LPS), lipoteichoic acid (LTA) and the cytoplasmic membrane (CM), the major components related to the mechanism of action of antimicrobial peptides.…”

“…(Aguilar-Toalá et al, 2019). These peptides provide microbicidal activity via physical disruption of a pathogen's membrane and subsequent leakage of cytoplasmic components, which greatly reduces the development of bacterial resistance because it is metabolically costly for the bacteria to mutate or repair the membrane's molecular constituents (Makovitzki et al, 2008;Wimley, 2010;Ong et al, 2013;Ma et al, 2016;Jiang et al, 2017;Dong et al, 2019). Thus, AMPs can also be widely used in agriculture and the food industry to replace the long-term and indiscriminate use of pesticides and antibiotics (Zanutto-Elgui et al, 2019).…”