SYNTHETIC HISTATIN ANALOGS WITH BROAD-SPECTRUM ANTIMICROBIAL ACTIVITY

Histatins are salivary histidine-rich cationic peptides, ranging from 7 to 38 amino acid residues in length, that exert a potent killing eff ect in vitro on Candida albicans. Starting from the C-terminal fungici dal domain of histatin 5 (residues 11-24, called dh-5) a number of sub stitution analogues were chemically synthesized to study the effect of amphipathicity of the peptide in helix conformation on candidacidal a ctivity. Single substitutions in dh-5 at several positions did not hav e any effect on fungicidal activity. However, multi-site substituted a nalogues (dhvar1 and dhvar2) exhibited a 6-fold increased activity ove r dh-5. In addition, dhvar1 and dhvar2 inhibited the growth of the sec ond most common yeast found in clinical isolates, Torulopsis glabinta, of oral-and non-oral pathogens such as Prevotella intermedia and Stre ptococcus mutans, and of a methicillin-resistant Staphylococcus aureus . In their broad-spectrum activity, dhvar1 and dhvar2 were comparable to magainins (PGLa and magainin 2), antimicrobial peptides of amphibia n origin, Both the fungicidal and the haemolytic activities of dhvar1, dhvar2 and magainins increased at decreasing ionic strength.