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

Abstract

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 O(2) consumption than vehicle-treated bacteria, and the decrease in O(2) 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.

Heme Oxygenase-1 and Carbon Monoxide Promote Burkholderia pseudomallei Infection

“…Recently, CORMs have been described to exert bactericidal (CORM-2, -3) or bacteriostatic (CORM-A1) activities against P. aeruginosa growth in vitro. However, only ruthenium-containing CORM-2 and -3 have been shown to possess potential therapeutic properties by increasing the survival of mice infected with P. aeruginosa (74,75). CORM-2 significantly reduced bacterial numbers in Salmonella-infected macrophages, as well (58).…”

Carbon Monoxide-releasing Antibacterial Molecules Target Respiration and Global Transcriptional Regulators

“…Note Added in Proof-Indeed, a very recent study (60) demonstrates that CORM-3 exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia.…”

Macrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activation

“…Chung et al (32) and Desmard et al. (39) demonstrate that CO-releasing molecules (CO-RM) confer host protection against infection, improving survival and preventing end-organ failure in response to bacterial infection, an effect associated with direct bacterial clearance and killing (39,40). When produced physiologically, however, CO has no direct Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood.…”

“…These effects mediated by CO were unrelated to direct bactericidal effects, as CO had no effect on bacterial growth in the absence of macrophages ( Figure 3E). effect on bacterial growth and survival unless administered exogenously at supraphysiologic conditions (39). Inhaled CO has been tested in large animals and phase I human trials and approved for use at up to 10% to 12% carboxyhemoglobin (COHb).…”