D-ENANTIOMERS OF 15-RESIDUE CECROPIN A-MELITTIN HYBRIDS

The all-D enantiomers of six 15-residue hybrids of cecropin A and meli ttin were synthesized. They contained the seven N-terminal residues of cecropin A, followed by eight residues from the N-terminal region of melittin. They were pure and of the correct composition and structure. The peptides were compared with their all-L enantiomers. The L and D isomer pairs were each exact mirror images by circular dichroism at se veral concentrations of hexafluoroisopropanol, and at 12 or 20% were h ighly helical. The L analogs were rapidly hydrolyzed by trypsin but th e D analogs were very resistant, making them suitable candidates for o rally active drugs. These 15-mers did not form ion channels in normal lipid bilayers made in decane, but those bilayers made in squalene wer e thinner and the peptides did form ion-conducting channels. The D/L p airs of peptides were very active antibiotics against five representat ive Gram-negative and Gram-positive bacteria. In each case the D and L isomers were essentially equally active within experimental error. Th is is interpreted to mean that the peptides do not act by tight intera ctions with chiral receptors, enzymes or lipids. The action of these p eptides against these organisms is best explained by self-aggregation and the formation of ion-conducting pores across bacterial membranes. (C) Munksgaard 1995.