Investigational Antibacterial Agent REP3123 Prevents Sporulation In Clostridium difficile
Replidyne's antibacterial candidate REP3123 is shown to in hibit growth and prevent spore-forming of the Gram-positive Clostridium difficile (C. difficile) bacterium without inhibiting other key organisms that are essential for normal intestinal functioning.
C. difficile-associated disease (CDAD), a major cause of morbidity among the elderly and hospitalized patients, is acquired by ingesting spores present in the environment that then grow and multiply in the gut. In preclinical studies, REP3123 was superior to two agents widely used to treat C. difficile infections, vancomycin and metronidazole, in preventing the organism from forming spores. The study results suggest that REP3123 has the potential to reduce the presence of spores in the intestine, subsequently preventing dissemination into the environment, thereby potentially reducing outbreak and relapse rates.
REP3123 is a new narrow spectrum antibacterial agent that in vitro prevents the growth of C. difficile by in hibiting an essential enzyme inthe bacterial cell called methionyl tRNA synthetase, which blocks the organism from synthesizing proteins. Methionyl tRNA synthetase is a novel target that has not been previously exploited by antibiotics and REP3123 shows no cross-resistance to currently marketed antibacterial agents. To determine the ability of REP3123 to prevent sporulation of C. difficile, four clinical isolates were studied including two epidemic BI/NAP1/027 strains identified in recent outbreaks in Quebec, Canada.
The BI/NAP1/027 outbreak strains produce greater amounts of toxins A and B, have increased sporulation capacity, and cause more severe disease and increased morbidity and mortality. All bacterial strains were grown in the presence of low concentrations (sub-minimum inhibitory concentrations or MICs) of either REP3123, vancomycin or metronidazole. Spores were quantified after 96 hours of drug exposure. All four strains of C. difficile varied in their ability to produce spores under the conditions evaluated in this study. At 0.5 times the MIC, REP3123 was the most effective agent at preventing the production of spores in all strains (equal to or less than 1% of spores after 96 hours of treatment). In contrast, sub-MICs of metronidazole promoted spore formation in three strains and vancomycin promoted sporulation in two strains. The ability of REP3123 to inhibit sporulation was concentration-dependent, with no spores detected at concentrations of 0.5 times the MIC. The FDA has not approved REP3123 for marketing in this or any other indication.
"CDAD is a challenging disease for many reasons, including the difficulty associated with eradication of Clostridium difficile and its spores from the environment," explained Stuart Johnson, M.D., Associate Professor of Medicine, Stritch School of Medicine, Loyola University and the Hines VA Medical Center in Chicago. "These results demonstrating that REP3123 has a direct impact on inhibiting spore-formation of C. difficile bacteria are highly promising and clinically relevant."
"Through a novel mechanism of action that inhibits growth and targets both sporulation and toxin production, REP3123 could be a future treatment option that tackles the main challenges associated with treating CDAD: high rates of relapse and new outbreaks," stated Kenneth J. Collins, Replidyne's President & CEO. "We are excited by the potential of REP3123 and look forward to its further development."
About Clostridium difficile
C. difficile is a Gram-positive anaerobic bacterium that causes C. difficile-associated disease (CDAD). According to the Centers for Disease Control and Prevention, CDAD is on the rise worldwide, both in terms of number of cases and severity of the disease. Most cases of CDAD occur in a hospital setting due to increased use of antibiotics and other chemotherapeutics that disrupt normal intestinal flora, an ageing population, and difficulty of eradicating C. difficile spores. However, more recently, CDAD has been acquired in the community setting where several outbreaks with increased mortality have occurred. The emergence of an epidemic, hypervirulent C. difficile strain (BI/NAP1, 027) that produces high levels of toxins poses a real threat to public health and demands improved infection control as well as novel treatment options.