Guanidinium-Functionalized Photodynamic Antibacterial Oligo(Thiophene)s
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MRS Advances © 2019 Materials Research Society DOI: 10.1557/adv.2019.359
Guanidinium-Functionalized Photodynamic Antibacterial Oligo(Thiophene)s Zhe Zhou, Cansu Ergene, Edmund F. Palermo* Materials Science and Engineering, Rensselaer Polytechnic Institute, 110 8th St., Troy, NY 12180
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.
INTRODUCTION Antibacterial agents are increasingly in high demand due to the rise of antibiotic resistance in pathogenic bacterial infections, combined with the decreasing number of new antibiotic drug approvals.1 Host defense peptides are one alterative approach to combat infectious disease.2 These peptides are components of the innate immune system in all multicellular organisms and they putatively kill bacteria by either by a direct mechanism that involves physical disruption of the bacterial cell membrane or by indirect immune-modulatory effects.3-5 The membrane disruption ability is due to their cationic and amphiphilic structures, which facilitate binding to anionic components of the bacterial cell envelope as well as insertion into the hydrophobic membrane core.6 Synthetic oligomers and polymers, primarily composed of cationic and hydrophobic groups, have been widely studied as mimics of HDP structure and function. 7 The chemical structure of cationic groups in these polymers/oligomers plays a key role as a determinant of biological activity.8-9 Whereas the majority of HDP-mimicry has focused on polymers with primary amines or quaternary ammonium salt (QAS) groups as the
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source of cationic charge,10 many HDPs are rich in cationic arginine residues, which display pendant guanidine groups. As such, several groups have investigated guanidinium-containing synthetic polymers as a strategy to enhance the binding to anionic membranes, for applications as antibacterials and as delivery vehicles.11-14 Indeed, the guanid
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