title: Rational Design of Single-Chain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria.
abstract: Infections caused by multidrug-resistant bacteria are on the rise and, therefore, new antimicrobial agents are required to prevent the onset of a postantibiotic era. In this study, we develop new antimicrobial compounds in the form of single-chain polymeric nanoparticles (SCPNs) that exhibit excellent antimicrobial activity against Gram-negative bacteria (e.g., Pseudomonas aeruginosa) at micromolar concentrations (e.g., 1.4 μM) and remarkably kill ≥99.99% of both planktonic cells and biofilm within an hour. Linear random copolymers, which comprise oligoethylene glycol (OEG), hydrophobic, and amine groups, undergo self-folding in aqueous systems due to intramolecular hydrophobic interactions to yield these SCPNs. By systematically varying the hydrophobicity of the polymer, we can tune the extent of cell membrane wall disruption, which in turn governs the antimicrobial activity and rate of resistance acquisition in bacteria. We also show that the incorporation of OEG groups into the polymer design is essential in preventing complexation with proteins in biological medium, thereby maintaining the antimicrobial efficacy of the compound even in in vivo mimicking conditions. In comparison to the last-resort antibiotic colistin, our lead agents have a higher therapeutic index (by ca. 2-3 times) and hence better biocompatibility. We believe that the SCPNs developed here have potential for clinical applications and the information pertaining to their structure-activity relationship will be valuable toward the general design of synthetic antimicrobial (macro)molecules.
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, UNSW Australia , Sydney, NSW 2052, Australia.
authors.forename: Thuy-Khanh
authors.initials: TK
authors.lastname: Nguyen
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Shu Jie
authors.initials: SJ
authors.lastname: Lam
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, NSW 2052, Australia.
authors.forename: Kitty K K
authors.initials: KK
authors.lastname: Ho
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, NSW 2052, Australia.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Greg G
authors.identifier: 0000-0003-2771-9675
authors.initials: GG
authors.lastname: Qiao
authors.affiliation: Centre for Marine Bio-Innovation, School of Biological, Earth and Environmental Sciences, UNSW Australia , Sydney, NSW 2052, Australia.
authors.forename: Suhelen
authors.initials: S
authors.lastname: Egan
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, UNSW Australia , Sydney, NSW 2052, Australia.
authors.forename: Cyrille
authors.identifier: 0000-0002-4564-4702
authors.initials: C
authors.lastname: Boyer
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, UNSW Australia , Sydney, NSW 2052, Australia.
authors.forename: Edgar H H
authors.identifier: 0000-0001-5151-5045
authors.initials: EH
authors.lastname: Wong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D002460:Cell Line; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000502:physiology; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D053758:Nanoparticles / Q000737:chemistry; D010933:Plankton / Q000187:drug effects*; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011108:Polymers
keywords: RAFT polymerization; antibiotics; biofilm; self-folding; single-chain polymeric nanoparticles