title: Insight into membrane selectivity of linear and branched polyethylenimines and their potential as biocides for advanced wound dressings.
abstract: We report here structure-property relationship between linear and branched polyethylene imines by examining their antimicrobial activities against wide range of pathogens. Both the polymers target the cytoplasmic membrane of bacteria and yeasts, eliciting rapid microbicidal properties. Using multiscale molecular dynamic simulations, we showed that, in both fully or partially protonated forms LPEI discriminates between mammalian and bacterial model membranes whereas BPEI lacks selectivity for both the model membranes. Simulation results suggest that LPEI forms weak complex with the zwitterionic lipids whereas the side chain amino groups of BPEI sequester the zwitterionic lipids by forming tight complex. Consistent with these observations, label-free cell impedance measurements, cell viability assays and high content analysis indicate that BPEI is cytotoxic to human epithelial and fibroblasts cells. Crosslinking of BPEI onto electrospun gelatin mats attenuate the cytotoxicity for fibroblasts while retaining the antimicrobial activity against Gram-positive and yeasts strains. PEI crosslinked gelatin mats elicit bactericidal activity by contact-mediated killing and durable to leaching for 7days. The potent antimicrobial activity combined with enhanced selectivity of the crosslinked ES gelatin mats would expand the arsenel of biocides in the management of superficial skin infections. The contact-mediated microbicidal properties may avert antimicrobial resistance and expand the diversity of applications to prevent microbial contamination.
  
  
  
  Current commercially available advanced wound dressings are either impregnated with metallic silver or silver salts which have side effects or may not avert antimicrobial resistance. In this article, we have used multidisciplinary approach comprising of computational, chemical and biological methods to understand the antimicrobial properties and biocompatibility of linear (LPEI) and branched (BPEI) polyethylenimines. We then applied this knowledge to develop dual purpose wound dressings containing these polymers, which encourages healing while maintain antimicrobial activity. In addition, the approach can be expanded to rationalize the antimicrobial vs. cytotoxicity of other cationic polymers and the method of crosslinking would enhance their potentials as biocides for advanced materials.
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore.
authors.forename: Stephen John
authors.initials: SJ
authors.lastname: Fox
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore 636921, Singapore.
authors.forename: Mobashar Hussain Urf Turabe
authors.initials: MH
authors.lastname: Fazil
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore.
authors.forename: Chetna
authors.initials: C
authors.lastname: Dhand
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore.
authors.forename: Mayandi
authors.initials: M
authors.lastname: Venkatesh
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore.
authors.forename: Eunice Tze Leng
authors.initials: ET
authors.lastname: Goh
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore.
authors.forename: Sriram
authors.initials: S
authors.lastname: Harini
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore.
authors.forename: Christo
authors.initials: C
authors.lastname: Eugene
authors.affiliation: Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine & Surgery, University of Missouri, Columbia, USA.
authors.forename: Rayne Rui
authors.initials: RR
authors.lastname: Lim
authors.affiliation: Department of Mechanical Engineering, National University of Singapore, Singapore 117576, Singapore.
authors.forename: Seeram
authors.initials: S
authors.lastname: Ramakrishna
authors.affiliation: Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine & Surgery, University of Missouri, Columbia, USA.
authors.forename: Shyam Sunder
authors.initials: SS
authors.lastname: Chaurasia
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore; SRP in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore. Electronic address: chandra@bii.a-star.edu.sg.
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Verma
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore 636921, Singapore. Electronic address: nkverma@ntu.edu.sg.
authors.forename: Navin Kumar
authors.initials: NK
authors.lastname: Verma
authors.affiliation: Institute of Materials Research & Engineering, A∗STAR, 2 Fusionopolis Way, Innovis, #08-03, Singapore 138634, Singapore. Electronic address: lohxj@imre.a-star.edu.sg.
authors.forename: Xian Jun
authors.initials: XJ
authors.lastname: Loh
authors.affiliation: Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore 169856, Singapore; SRP in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore. Electronic address: lakshminarayanan.rajamani@seri.com.sg.
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001458:Bandages; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry; D004202:Disinfectants / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005780:Gelatin / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008567:Membranes, Artificial; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D011094:Polyethyleneimine / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D034421:Sus scrofa
chemical_list: D000900:Anti-Bacterial Agents; D003432:Cross-Linking Reagents; D004202:Disinfectants; D007211:Indoles; D008567:Membranes, Artificial; D011108:Polymers; C568283:polydopamine; D005780:Gelatin; D011094:Polyethyleneimine
keywords: Contact-mediated antibacterials; Electrospinning; Membrane selectivity; Molecular dynamics; Polyethylenimine