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Antimicrobial Agents and Chemotherapy, August 2005, p. 3109-3113, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3109-3113.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

3',5'-Cyclic Diguanylic Acid Reduces the Virulence of Biofilm-Forming Staphylococcus aureus Strains in a Mouse Model of Mastitis Infection

Eric Brouillette,1 Mamoru Hyodo,2 Yoshihiro Hayakawa,2 David K. R. Karaolis,3 and François Malouin1*

Centre d'Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1K 2R1,1 Graduate School of Information Science/Human Informatics and CREST/JST, Nagoya University, Nagoya 464-8601, Japan,2 Department of Epidemiology and Preventive Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 212013

Received 25 January 2005/ Returned for modification 22 March 2005/ Accepted 17 May 2005

The cyclic dinucleotide 3',5'-cyclic diguanylic acid (c-di-GMP) is a naturally occurring small molecule that regulates important signaling systems in bacteria. We have recently shown that c-di-GMP inhibits Staphylococcus aureus biofilm formation in vitro and its adherence to HeLa cells. We now report that c-di-GMP treatment has an antimicrobial and antipathogenic activity in vivo and reduces, in a dose-dependent manner, bacterial colonization by biofilm-forming S. aureus strains in a mouse model of mastitis infection. Intramammary injections of 5 and 50 nmol of c-di-GMP decreased colonization (bacterial CFU per gram of gland) by 0.79 (P > 0.05) and 1.44 (P < 0.01) logs, respectively, whereas 200-nmol doses allowed clearance of the bacteria below the detection limit with a reduction of more than 4 logs (P < 0.001) compared to the untreated control groups. These results indicate that cyclic dinucleotides potentially represent an attractive and novel drug platform which could be used alone or in combination with other agents or drugs in the prevention, treatment, or control of infection.

* Corresponding author. Mailing address: CEVDM, Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, Québec, Canada J1K 2R1. Phone: (819) 821-8000, ext. 1202. Fax: (819) 821-8049. E-mail: francois.malouin{at}usherbrooke.ca.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3109-3113, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3109-3113.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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