Pharmacodynamic synergy strictly dependent on the co-operative aggregation of enantiomers of cyclic peptides in the bacterial cell membrane

The antimicrobial activity of the peptide enantiomers cyclo[d-Tle-d-Lys-d-Tle-l-Ala-d-Tle-l-Ala-d-Tle-l-Ala] and cyclo[l-Tle-l-Lys-l-Tle-d-Ala-l-Tle-d-Ala-l-Tle-d-Ala] against Bacillus megaterium was investigated. Both these peptides showed very low activity in both an agar diffusion assay and a broth microdilution assay. However, when both peptides were present during the experiments a potent inhibition with an IC50 value of 2 μM was observed. Furthermore, the peptides also showed low hemolytic activity. Neither peptide had any hemolytic activity in concentrations up to 1 mM but when erythrocytes were exposed to both peptides a weak hemolytic activity could be observed with a HC50 value of 316 μM.