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ABSTRACT We synthesized precision oligomers of thiophene with cationic and hydrophobic side chains to mimic the charge, hydrophobicity, and molecular size of antibacterial host defense peptides (HDPs). In this study, the source of cationic charge was a guanidinium salt moiety intended to reflect the structure of arginine-rich HDPs. Due to the pi-conjugated oligo(thiophene) backbone structure, these compounds absorb visible light in aqueous solution and react with dissolved oxygen to produce highly biocidal reactive oxygen species (ROS). Thus, the compounds exert bactericidal activity in the dark with dramatically enhanced potency upon visible light illumination. We find that guanylation of primary amine groups enhanced the activity of the oligomers in the dark but also mitigated their light-induced activity enhancement. In addition, we also quantified their toxicity to mammalian cell membranes using a hemolysis assay with red blood cells, in the light and dark conditions. 

We utilized a templated ring-opening metathesis (TROM) strategy to synthesize a series of precision macrocyclic olefins, each containing two, three or four repeating units of a cyclooctene with pendant carboxylic acid side chains. The structures were confirmed by a combination of NMR spectroscopy, MALDI, and MALDI ms/ms fragmentation studies. In accordance with previous work, we found that cyclooctene monomers covalently tethered to precision oligo(thiophene)s yield exclusively macrocyclic products when subjected to the Grubbs 3 rd generation catalyst in highly dilute solution (10 −4 M in DCM, 0 °C). Upon hydrolytic liberation of the daughter oligo(olefin) product, further derivatization with cationic groups confers antibacterial and hemolytic activities. We compare the biological activity of these precision macrocycles to that of a polydisperse sample prepared by direct ROM in the absence of a template. Surprisingly, the relatively ill-defined, disperse mixture of oligomeric species exerted biological activity comparable to that of the precision oligomeric macrocycles, suggesting a remarkable degree of tolerance for heterogeneity. These findings provide nuance to the structure–activity relationships understood thus far for AMPs and their mimics, especially in the context of relatively underexplored macrocyclic compounds. 

We report the first example of a self-immolative polymer that exerts potent antibacterial activity combined with relatively low hemolytic toxicity. In particular, self-immolative poly(benzyl ether)s bearing pendant cationic ammonium groups and grafted poly(ethylene glycol) chains in their side chains were prepared via post-polymerization thiol–ene chemistry. These functional polymers undergo sensitive and specific triggered depolymerization into small molecules upon exposure to a designed stimulus (in this example, fluoride ions cleave a silyl ether end cap). The molar composition of the resulting statistical copolymers varied from 0 to 100% PEG side chains. The average molar mass of the pendant PEG chains was either 800 or 2000 g mol −1 . The antibacterial and hemolytic activities were evaluated as a function of copolymer composition. Strong bactericidal activity (low μg mL −1 MBC) was retained in the copolymers containing 25–50% PEG-800, whereas hemolytic toxicity monotonically decreased (up to HC 50 >1000 μg mL −1 ) with increasing PEG content. PEG-2000 was far less effective; both the MBC and HC 50 decreased to a comparable extent with increasing PEGylation. Overall, the best cell type selectivity index (HC 50 /MBC ∼ 28) was obtained for the copolymer containing ∼50% cysteamine and ∼50% PEG-800 side chains, as compared to the cationic homopolymer (HC 50 /MBC < 1). Thus, the systematic tuning of the PEG graft density and chain length effectively enhances the cell-type selectivity of these self-immolative polymers by orders of magnitude. 

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.