title: Tuning the biological activity profile of antibacterial polymers via subunit substitution pattern.
abstract: Binary nylon-3 copolymers containing cationic and hydrophobic subunits can mimic the biological properties of host-defense peptides, but relationships between composition and activity are not yet well understood for these materials. Hydrophobic subunits in previously studied examples have been limited mostly to cycloalkane-derived structures, with cyclohexyl proving to be particularly promising. The present study evaluates alternative hydrophobic subunits that are isomeric or nearly isomeric with the cyclohexyl example; each has four sp(3) carbons in the side chains. The results show that varying the substitution pattern of the hydrophobic subunit leads to relatively small changes in antibacterial activity but causes significant changes in hemolytic activity. We hypothesize that these differences in biological activity profile arise, at least in part, from variations among the conformational propensities of the hydrophobic subunits. The α,α,β,β-tetramethyl unit is optimal among the subunits we have examined, providing copolymers with potent antibacterial activity and excellent prokaryote vs eukaryote selectivity. Bacteria do not readily develop resistance to the new antibacterial nylon-3 copolymers. These findings suggest that variation in subunit conformational properties could be generally valuable in the development of synthetic polymers for biological applications.
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, #Department of Medical Microbiology and Immunology, and §Department of Medicine, University of Wisconsin , Madison, Wisconsin 53706, United States.
authors.forename: Runhui
authors.initials: R
authors.lastname: Liu
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Saswata
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Lemke
authors.forename: Zvi
authors.initials: Z
authors.lastname: Hayouka
authors.forename: Clara
authors.initials: C
authors.lastname: Chow
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Welch
authors.forename: Bernard
authors.initials: B
authors.lastname: Weisblum
authors.forename: Kristyn S
authors.initials: KS
authors.lastname: Masters
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001409:Bacillus cereus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D019779:Salmonella enterica / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D009757:Nylons; D011108:Polymers