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Antimicrobial Agents and Chemotherapy, August 2008, p. 2870-2881, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00203-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Copper and Quaternary Ammonium Cations Exert Synergistic Bactericidal and Antibiofilm Activity against Pseudomonas aeruginosa{triangledown}

Joe J. Harrison,1,2 Raymond J. Turner,1* Daniel A. Joo,1,2 Michelle A. Stan,1,2 Catherine S. Chan,1 Nick D. Allan,3 Helen A. Vrionis,1 Merle E. Olson,3 and Howard Ceri1,2*

Department of Biological Sciences, University of Calgary, 2500 University Drive N.W., Calgary, Alberta, Canada T2N 1N4,1 Biofilm Research Group, University of Calgary, 2500 University Drive N.W., Calgary, Alberta, Canada T2N 1N4,2 Innovotech Incorporated, Suite 101, 2011 94th Street, Edmonton, Alberta, Canada TGN 1H13

Received 12 February 2008/ Returned for modification 29 April 2008/ Accepted 26 May 2008

Biofilms are slimy aggregates of microbes that are likely responsible for many chronic infections as well as for contamination of clinical and industrial environments. Pseudomonas aeruginosa is a prevalent hospital pathogen that is well known for its ability to form biofilms that are recalcitrant to many different antimicrobial treatments. We have devised a high-throughput method for testing combinations of antimicrobials for synergistic activity against biofilms, including those formed by P. aeruginosa. This approach was used to look for changes in biofilm susceptibility to various biocides when these agents were combined with metal ions. This process identified that Cu2+ works synergistically with quaternary ammonium compounds (QACs; specifically benzalkonium chloride, cetalkonium chloride, cetylpyridinium chloride, myristalkonium chloride, and Polycide) to kill P. aeruginosa biofilms. In some cases, adding Cu2+ to QACs resulted in a 128-fold decrease in the biofilm minimum bactericidal concentration compared to that for single-agent treatments. In combination, these agents retained broad-spectrum antimicrobial activity that also eradicated biofilms of Escherichia coli, Staphylococcus aureus, Salmonella enterica serovar Cholerasuis, and Pseudomonas fluorescens. To investigate the mechanism of action, isothermal titration calorimetry was used to show that Cu2+ and QACs do not interact in aqueous solutions, suggesting that each agent exerts microbiological toxicity through independent biochemical routes. Additionally, Cu2+ and QACs, both alone and in combination, reduced the activity of nitrate reductases, which are enzymes that are important for normal biofilm growth. Collectively, the results of this study indicate that Cu2+ and QACs are effective combinations of antimicrobials that may be used to kill bacterial biofilms.

* Corresponding author. Mailing address: Department of Biological Sciences, University of Calgary, 2500 University Drive N.W., Calgary, Alberta, Canada T2N 1N4. Phone for Raymond J. Turner: (403) 220-4308. Fax: (403) 289-9311. E-mail: turnerr{at}ucalgary.ca. Phone for Howard Ceri: (403) 220-6960. Fax: (403) 289-9311. E-mail: ceri{at}ucalgary.ca

{triangledown} Published ahead of print on 2 June 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2870-2881, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00203-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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