title: Synthesis and Evaluation of Ciprofloxacin-Nitroxide Conjugates as Anti-Biofilm Agents.
abstract: As bacterial biofilms are often refractory to conventional antimicrobials, the need for alternative and/or novel strategies for the treatment of biofilm related infections has become of paramount importance. Herein, we report the synthesis of novel hybrid molecules comprised of two different hindered nitroxides linked to the piperazinyl secondary amine of ciprofloxacin via a tertiary amine linker achieved utilising reductive amination. The corresponding methoxyamine derivatives were prepared alongside their radical-containing counterparts as controls. Subsequent biological evaluation of the hybrid compounds on preformed P. aeruginosa flow cell biofilms divulged significant dispersal and eradication abilities for ciprofloxacin-nitroxide hybrid compound 10 (up to 95% eradication of mature biofilms at 40 μM). Importantly, these hybrids represent the first dual-action antimicrobial-nitroxide agents, which harness the dispersal properties of the nitroxide moiety to circumvent the well-known resistance of biofilms to treatment with antimicrobial agents.
authors.affiliation: ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Faculty of Science and Engineering, Queensland University of Technology, Queensland 4001, Australia. a.verderosa@hdr.qut.edu.au.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Verderosa
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. sarah@hancocklab.com.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mansour
authors.affiliation: Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. cfuente@mit.edu.|Research Laboratory of Electronics, Department of Biological Engineering, Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge 02139, MA, USA. cfuente@mit.edu.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. cfuente@mit.edu.|Harvard Biophysics Program, Harvard University, Boston, MA 02115, USA. cfuente@mit.edu.
authors.forename: César
authors.initials: C
authors.lastname: de la Fuente-Núñez
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. bob@hancocklab.com.
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.affiliation: ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Faculty of Science and Engineering, Queensland University of Technology, Queensland 4001, Australia. k.fairfull-smith@qut.edu.au.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Fairfull-Smith
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002939:Ciprofloxacin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*; D011550:Pseudomonas aeruginosa / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D009569:Nitric Oxide; D002939:Ciprofloxacin
keywords: antibiotic; biofilm; ciprofloxacin; nitroxide; radical