title: Long hydrophilic-and-cationic polymers: a different pathway toward preferential activity against bacterial over mammalian membranes.
abstract: We show that simply converting the hydrophobic moiety of an antimicrobial peptide (AMP) or synthetic mimic of AMPs (SMAMP) into a hydrophilic one could be a different pathway toward membrane-active antimicrobials preferentially acting against bacteria over host cells. Our biostatistical analysis on natural AMPs indicated that shorter AMPs tend to be more hydrophobic, and the hydrophilic-and-cationic mutants of a long AMP experimentally demonstrated certain membrane activity against bacteria. To isolate the effects of antimicrobials' hydrophobicity and systematically examine whether hydrophilic-and-cationic mutants could inherit the membrane activity of their parent AMPs/SMAMPs, we constructed a minimal prototypical system based on methacrylate-based polymer SMAMPs and compared the antibacterial membrane activity and hemolytic toxicity of analogues with and without the hydrophobic moiety. Antibacterial assays showed that the hydrophobic moiety of polymer SMAMPs consistently promoted the antibacterial activity but diminished in effectiveness for long polymers, and the resultant long hydrophilic-and-cationic polymers were also membrane active against bacteria. What distinguished these long mutants from their parent SMAMPs were their drastically reduced hemolytic toxicities and, as a result, strikingly enhanced selectivity. Similar toxicity reduction was observed with the hydrophilic-and-cationic mutants of long AMPs. Taken together, our results suggest that long hydrophilic-and-cationic polymers could offer preferential membrane activity against bacteria over host cells, which may have implications in future antimicrobial development.
authors: CAS Key Laboratory of Soft Matter Chemistry, ¶Department of Materials Science and Engineering, #Department of Polymer Science and Engineering, ⊥CAS Key Laboratory of Materials for Energy Conversion, University of Science and Technology of China , Hefei, Anhui 230026 P.R. China.
authors: Xin
authors: X
authors: Yang
authors: Kan
authors: K
authors: Hu
authors: Guantai
authors: G
authors: Hu
authors: Danyao
authors: D
authors: Shi
authors: Yunjiang
authors: Y
authors: Jiang
authors: Liwei
authors: L
authors: Hui
authors: Rui
authors: R
authors: Zhu
authors: Yuntao
authors: Y
authors: Xie
authors: Lihua
authors: L
authors: Yang
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000737:chemistry / Q000254:growth & development*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects*; D011109:Polymethacrylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid