Mode of Action and Bactericidal Properties of Surotomycin against Growing and Nongrowing Clostridium difficile

Surotomycin (CB-183,315), a cyclic lipopeptide, is in phase 3 clinical development for the treatment of Clostridium difficile infection. We report here the further characterization of the in vitro mode of action of surotomycin, including its activity against growing and nongrowing C. difficile. This was assessed through time-kill kinetics, allowing a determination of the effects on the membrane potential and permeability and macromolecular synthesis in C. difficile. Against representative strains of C. difficile, surotomycin displayed concentration-dependent killing of both logarithmic-phase and stationary-phase cultures at a concentration that was <= 16x the MIC. Exposure resulted in the inhibition of macromolecular synthesis (in DNA, RNA, proteins, and cell wall). At bactericidal concentrations, surotomycin dissipated the membrane potential of C. difficile without changes to the permeability of propidium iodide. These observations are consistent with surotomycin acting as a membrane-active antibiotic, exhibiting rapid bactericidal activities against growing and nongrowing C. difficile.