title: Side Chain Degradable Cationic-Amphiphilic Polymers with Tunable Hydrophobicity Show in Vivo Activity.
abstract: Cationic-amphiphilic antibacterial polymers with optimal amphiphilicity generally target the bacterial membranes instead of mammalian membranes. To date, this balance has been achieved by varying the cationic charge or side chain hydrophobicity in a variety of cationic-amphiphilic polymers. Optimal hydrophobicity of cationic-amphiphilic polymers has been considered as the governing factor for potent antibacterial activity yet minimal mammalian cell toxicity. However, the concomitant role of hydrogen bonding and hydrophobicity with constant cationic charge in the interactions of antibacterial polymers with bacterial membranes is not understood. Also, degradable polymers that result in nontoxic degradation byproducts offer promise as safe antibacterial agents. Here we show that amide- and ester (degradable)-bearing cationic-amphiphilic polymers with tunable side chain hydrophobicity can modulate antibacterial activity and cytotoxicity. Our results suggest that an amide polymer can be a potent antibacterial agent with lower hydrophobicity whereas the corresponding ester polymer needs a relatively higher hydrophobicity to be as effective as its amide counterpart. Our studies reveal that at higher hydrophobicities both amide and ester polymers have similar profiles of membrane-active antibacterial activity and mammalian cell toxicity. On the contrary, at lower hydrophobicities, amide and ester polymers are less cytotoxic, but the former have potent antibacterial and membrane activity compared to the latter. Incorporation of amide and ester moieties made these polymers side chain degradable, with amide polymers being more stable than the ester polymers. Further, the polymers are less toxic, and their degradation byproducts are nontoxic to mice. More importantly, the optimized amide polymer reduces the bacterial burden of burn wound infections in mice models. Our design introduces a new strategy of interplay between the hydrophobic and hydrogen bonding interactions keeping constant cationic charge density for developing potent membrane-active antibacterial polymers with minimal toxicity to mammalian cells.
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Jakkur, Bangalore 560064, India.
authors.forename: Divakara S S M
authors.initials: DS
authors.lastname: Uppu
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Jakkur, Bangalore 560064, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Samaddar
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Jakkur, Bangalore 560064, India.
authors.forename: Jiaul
authors.initials: J
authors.lastname: Hoque
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Jakkur, Bangalore 560064, India.
authors.forename: Mohini M
authors.initials: MM
authors.lastname: Konai
authors.affiliation: ICAR-National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI) , Ramagondanahalli, Yelahanka, Bengaluru 560064, India.
authors.forename: Paramanandham
authors.initials: P
authors.lastname: Krishnamoorthy
authors.affiliation: ICAR-National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI) , Ramagondanahalli, Yelahanka, Bengaluru 560064, India.
authors.forename: Bibek R
authors.initials: BR
authors.lastname: Shome
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Jakkur, Bangalore 560064, India.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D002412:Cations; D011108:Polymers