Ciprofloxacin-nitroxide hybrids with potential for biofilm control

Anthony D Verderosa; César de la Fuente-Núñez; Sarah C Mansour; Jicong Cao; Timothy K Lu; Robert E W Hancock; Kathryn E Fairfull-Smith

doi:10.1016/j.ejmech.2017.06.058

Ciprofloxacin-nitroxide hybrids with potential for biofilm control

Eur J Med Chem. 2017 Sep 29:138:590-601. doi: 10.1016/j.ejmech.2017.06.058. Epub 2017 Jun 28.

Authors

Anthony D Verderosa¹, César de la Fuente-Núñez², Sarah C Mansour³, Jicong Cao², Timothy K Lu², Robert E W Hancock³, Kathryn E Fairfull-Smith⁴

Affiliations

¹ ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Faculty of Science and Engineering, Queensland University of Technology, Queensland 4001, Australia.
² Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, United States; Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, United States; Department of Biological Engineering, Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States; Harvard Biophysics Program, Harvard University, Boston, MA, United States; The Center for Microbiome Informatics and Therapeutics, Cambridge, MA, United States.
³ Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
⁴ ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Faculty of Science and Engineering, Queensland University of Technology, Queensland 4001, Australia. Electronic address: k.fairfull-smith@qut.edu.au.

PMID: 28709125
DOI: 10.1016/j.ejmech.2017.06.058

Abstract

As bacterial biofilms display extreme tolerance to conventional antibiotic treatments, it has become imperative to develop new antibacterial strategies with alternative mechanisms of action. Herein, we report the synthesis of a series of ciprofloxacin-nitroxide conjugates and their corresponding methoxyamine derivatives in high yield. This was achieved by linking various nitroxides or methoxyamines to the secondary amine of the piperazine ring of ciprofloxacin using amide bond coupling. Biological evaluation of the prepared compounds on preformed P. aeruginosa biofilms in flow cells revealed substantial dispersal with ciprofloxacin-nitroxide hybrid 25, and virtually complete killing and removal (94%) of established biofilms in the presence of ciprofloxacin-nitroxide hybrid 27. Compounds 25-28 were shown to be non-toxic in both human embryonic kidney 293 (HEK 293) cells and human muscle rhabdomyosarcoma (RD) cells at concentrations up to 40 μM. Significantly, these hybrids demonstrate the potential of antimicrobial-nitroxide agents to overcome the resistance of biofilms to antimicrobials via stimulation of biofilm dispersal or through direct cell killing.

Keywords: Antibiotic; Biofilm; Ciprofloxacin; Nitroxide; Radical.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Biofilms / drug effects*
Cell Line, Tumor
Ciprofloxacin / chemistry
Ciprofloxacin / pharmacology*
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Microbial Sensitivity Tests
Molecular Structure
Nitrogen Oxides / chemistry
Nitrogen Oxides / pharmacology*
Pseudomonas aeruginosa / drug effects*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Nitrogen Oxides
Ciprofloxacin