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A carbon monoxide-releasing molecule (CORM-3) exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia

Mathieu Desmard^*,¶,1, Kelly S. Davidge, Odile Bouvet, Didier Morin, Damien Roux, Roberta Foresti^**,, Jean D. Ricard^,||, Erick Denamur, Robert K. Poole, Philippe Montravers^¶, Roberto Motterlini^**, and Jorge Boczkowski^*,#

^* Inserm, U700, and

Inserm, U722, Université Paris 7, Faculté de Médecine, Paris, France;

Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, UK;

Inserm, U841 équipe 3, Université Paris 12, Faculté de Médecine, Creteil, France;

^|| Réanimation Médicale, Assistance Publique–Hôpitaux de Paris, Hôpital Louis Mourier, Colombes, France;

^¶ Département Anesthésie-Réanimation Chirurgicale and

^# Centre d’Investigation Clinique 07, Assistance Publique–Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Paris, France;

^** Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK; and

Department of Drug Discovery and Development, Italian Institute of Technology, Genova, Italy

¹Correspondence: Inserm U700, Faculté de Médecine Paris 7, site X. Bichat, BP416, 75870 Paris Cedex 18, France. E-mail: desmardmathieu{at}yahoo.fr

The search for new molecules to fight Pseudomonas aeruginosa is of paramount importance. Carbon monoxide (CO) is known to act as an effective inhibitor of the respiratory chain in P. aeruginosa, but the practical use of this gas as an antibacterial molecule is hampered by its toxicity and difficulty to manipulate. Here, we show that a water-soluble CO releaser (CORM-3) possesses bactericidal properties against laboratory and antibiotic-resistant P. aeruginosa. CORM-3 reduced the bacterial count by 4 logs 180 min after in vitro treatment. CORM-3-treated bacteria had a lower O₂ consumption than vehicle-treated bacteria, and the decrease in O₂ consumption temporally preceded the bactericidal action of CORM-3. These results support the hypothesis that the antimicrobial effect of CORM-3 is mediated by an interaction of CO liberated by the carrier with the bacterial respiratory chain. The antibacterial effect occurred at concentrations of CORM-3 that are 50-fold lower than toxic concentrations for eukaryotic cells. CORM-3 treatment compared to vehicle treatment decreased bacterial counts in the spleen and increased survival in immunocompetent and immunosuppressed mice following P. aeruginosa bacteremia. Our results suggest that CORMs could form the basis for developing a new therapeutic strategy against P. aeruginosa-induced infection.—Desmard, M., Davidge, K. S., Bouvet, O., Morin, D., Roux, D., Foresti, R., Ricard, J. D., Denamur, E., Poole, R. K., Montravers, P., Motterlini, R., Boczkowski, J. A carbon monoxide-releasing molecule (CORM-3) exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia.

Key Words: pharmacology • anti-infective agents • sepsis • microbiology

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				K. S. Davidge, G. Sanguinetti, C. H. Yee, A. G. Cox, C. W. McLeod, C. E. Monk, B. E. Mann, R. Motterlini, and R. K. Poole Carbon Monoxide-releasing Antibacterial Molecules Target Respiration and Global Transcriptional Regulators J. Biol. Chem., February 13, 2009; 284(7): 4516 - 4524. [Abstract] [Full Text] [PDF]