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Antimicrobial Agents and Chemotherapy, March 2005, p. 1029-1038, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1029-1038.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

c-di-GMP (3'-5'-Cyclic Diguanylic Acid) Inhibits Staphylococcus aureus Cell-Cell Interactions and Biofilm Formation

David K. R. Karaolis,1* Mohammed H. Rashid,1 Rajanna Chythanya,1 Wensheng Luo,2 Mamoru Hyodo,3 and Yoshihiro Hayakawa3

Department of Epidemiology and Preventive Medicine,1 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland,2 Graduate School of Information Science/Human Informatics and CREST/JST, Nagoya University, Nagoya, Japan3

Received 23 June 2004/ Returned for modification 3 August 2004/ Accepted 4 November 2004

Staphylococcus aureus is an important pathogen of humans and animals, and antibiotic resistance is a public health concern. Biofilm formation is essential in virulence and pathogenesis, and the ability to resist antibiotic treatment results in difficult-to-treat and persistent infections. As such, novel antimicrobial approaches are of great interest to the scientific, medical, and agriculture communities. We recently proposed that modulating levels of the cyclic dinucleotide signaling molecule, c-di-GMP (cyclic diguanylate [3',5'-cyclic diguanylic acid], cGpGp), has utility in regulating phenotypes of prokaryotes. We report that extracellular c-di-GMP shows activity against human clinical and bovine intramammary mastitis isolates of S. aureus, including methicillin-resistant S. aureus (MRSA) isolates. We show that chemically synthesized c-di-GMP is soluble and stable in water and physiological saline and stable following boiling and exposure to acid and alkali. Treatment of S. aureus with extracellular c-di-GMP inhibited cell-to-cell (intercellular) adhesive interactions in liquid medium and reduced (>50%) biofilm formation in human and bovine isolates compared to untreated controls. c-di-GMP inhibited the adherence of S. aureus to human epithelial HeLa cells. The cyclic nucleotide analogs cyclic GMP and cyclic AMP had a lesser inhibitory effect on biofilms, while 5'-GMP had no major effect. We propose that cyclic dinucleotides such as c-di-GMP, used either alone or in combination with other antimicrobial agents, represent a novel and attractive approach in the development of intervention strategies for the prevention of biofilms and the control and treatment of infection.

* Corresponding author. Mailing address: Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201. Phone: (410) 706-4718. Fax: (410) 706-4581. E-mail: karaolis{at}umaryland.edu.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1029-1038, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1029-1038.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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