Antimicrobial polymers prepared by ROMP with unprecedented selectivity: a molecular construction kit approach

Abstract

Synthetic Mimics of Antimicrobial Peptides (SMAMPs) imitate natural host-defense peptides, a vital component of the body's immune system. This work presents a molecular construction kit that allows the easy and versatile synthesis of a broad variety of facially amphiphilic oxanorbornene-derived monomers. Their ring-opening metathesis polymerization (ROMP) and deprotection provide several series of SMAMPs. Using amphiphilicity, monomer feed ratio, and molecular weight as parameters, polymers with 533 times higher selectivitiy (selecitviy = hemolytic concentration/minimum inhibitory concentration) for bacteria over mammalian cells were discovered. Some of these polymers were 50 times more selective for Gram-positive over Gram-negative bacteria while other polymers surprisingly showed the opposite preference. This kind of "double selectivity" (bacteria over mammalian and one bacterial type over another) is unprecedented in other polymer systems and is attributed to the monomer's facial amphiphilicity.

Figure 1

“Construction kit” approach to obtain facially amphiphilic monomers and polymers. Just as with a Lego construction kit, the synthetic approach presented here allows the independent combination of a hydrophilic (blue), a hydrophobic (green), and a polymerizable (yellow) part of the monomer to yield a whole set of antimicrobial polymers with tunable activity and selectivity.

Figure 2

Biological data (MIC₉₀ for E. coli and S. aureus, and HC₅₀ for red blood cells) for the homopolymers. (a) 3000 g/mol series, (b) 10 000 g/mol series.

Figure 3

Characterization of propyl oligomers. (a) GPC traces and (b) MALDI-TOF MS peaks and distributions.

Figure 4

Biological data (MIC₉₀ for E. coli and S. aureus, and HC₅₀ for red blood cells) for the propyl oligomer series.

Figure 5

Biological data (MIC₉₀ for E. coli and S. aureus, and HC₅₀ for red blood cells) for the copolymers. (a) Ethyl-propyl series, (b) methylethyl series, and (c) methyl-propyl series. Sample labeling: e.g., E1/P9 is a copolymer with 10 mol% ethyl and 90 mol% propyl monomer.

Scheme 1

Monomer Synthesis^{a a} The hydrophobic component of the facially amphiphilic monomer is introduced in the second reaction step (R = methyl, ethyl, propyl, butyl, isopentyl, or hexyl), and the protected hydrophilic moiety is attached in the last step.

Scheme 2

Polymer Synthesis^{a a} ROMP polymerization is followed by polymer analogous hydrolysis with trifluoroacetic acid to yield the facially amphiphilic polymer.