Histatin 5 is the most studied member of the salivary histatin family and the one responsible for most of the candidacidal activity of human saliva. The supplied sequence is strongly cationic, rich in histidine, lysine and arginine, which is what drives its initial association with the fungal cell surface. Its killing mechanism is unusual among antimicrobial peptides and is the reason it attracts sustained interest. Rather than simply lysing the membrane, histatin 5 is taken up into the fungal cytoplasm and acts intracellularly. Uptake by Candida albicans requires the Ssa2 protein and has been shown to depend on binding at non-conventional sites within its ATPase domain, and the potassium transporter Trk1p mediates the activity of cysteine-free cationic peptides of this class. Imaging work established that the peptide causes a spatially restricted disruption of the cell surface that permits rapid entry into the cytoplasm rather than general permeabilisation, and comparative studies have found that histatin 5 and human neutrophil defensin 1 kill C. albicans through shared pathways. Two practical points follow. Because the mechanism is receptor- and transporter-dependent rather than purely physicochemical, activity is sensitive to ionic strength and to the metabolic state of the target cells, so assay buffer composition matters more than for a simple lytic peptide. And because killing requires uptake, mutants lacking the relevant transport machinery can be resistant without any change to the peptide itself. | 