Histatins are a group of small, cationic, antifungal peptides present in human 
saliva. A previous molecular modeling analysis suggested structural similarity 
between the Phe14-His15 and His18-His19 dipeptide sequences in histatin-5 
(Hsn-5; a 24-amino-acid polypeptide) and the sequence of miconazole (one of the 
azole-based antifungal therapeutic agents), implying that the mechanisms of 
killing of Candida albicans by these two molecules may be similar. To further 
elaborate on this observation, we have produced two variants of Hsn-5 in which 
Phe14-His15 or His18-His19 dipeptide sequences were replaced by Ala-Ala 
(F14A/H15A and H18A/H19A) to eliminate the phenyl and imidazole rings of the 
side chains and assessed their candidacidal activities against C. albicans. In 
addition, we tested azole-resistant C. albicans and Candida glabrata strains for 
their susceptibilities to Hsn-5. Analysis of the purified recombinant proteins 
for their candidacidal activities indicated that both variants were 
significantly less effective (the molar concentrations required to kill half of 
the maximum number of cells [ED50s], approximately 67 and approximately 149 
microM for F14A/H15A and H18A/H19A, respectively) than the unaltered Hsn-5 
(ED50, approximately 8 microM) at killing C. albicans, suggesting that the two 
dipeptide sequences are important for the candidacidal activity of Hsn-5. 
Assessment of the candidacidal activity of Hsn-5 with the well-characterized 
azole-resistant strains of C. albicans and C. glabrata, however, suggested that 
the mode of action of histatins against Candida is distinct from that of 
azole-based antifungal agents because Hsn-5 kills both azole-sensitive and 
azole-resistant strains equally well.