Human serum binding and its effect on the pharmacodynamics of the lantibiotic MU1140

The degree of MU1140 binding to human serum was measured and the effect of serum on MU1140 pharmacodynamics against Streptococcus pneumoniae and Staphylococcus aureus was investigated. 92.7%+/- 2.0% of total MU1140 was bound to serum components as determined by ultrafiltration when tested in the concentration range 6.25-200 mu g/ml. MIC and time-kill studies were used to study the effect of serum on the dynamics of MU1140. Serum inhibited MW 140 activity against S. pneumoniae but was found to enhance its activity against S. aureus. This phenomenon has not been reported for any other lantibiotic. Time-kill studies of MU 1140 against S. aureus in various concentrations of serum revealed that the greatest bactericidal effect was observed at the lowest serum concentration. Mathematical modeling was used to quantify serum augmentation of MU 1140 activity against S. aureus. Serum, at the lowest concentration, was shown to decrease MU1140 EC50 against S. aureus by an order of magnitude. The data suggests that unbound MU1140 comprise the pharmacologically active fraction. Further, these findings suggest the possible existence of a complex dual inhibition and augmentation effect of serum on MU1140's activity against S. aureus. The molecular mechanism responsible for the synergistic action of human serum on MU1140's activity against S. aureus remains to be elucidated. (C) 2010 Elsevier B.V. All rights reserved.