Insights into the Mode of Action of the Two-Peptide Lantibiotic Haloduracin

Haloduracin, a recently discovered two-peptide lantibiotic composed of the post-translationally modified peptides Hal alpha and Hal beta, is shown to have high potency against a range of Gram-positive bacteria and to Inhibit spore outgrowth of Bacillus anthracis. The two peptides display optimal activity In a 1:1 stoichiometry and have efficacy similar to that of the commercially used lantibiotic nisin. However, haloduracin is more stable at pH 7 than nisin. Despite significant structural differences between the two peptides of haloduracin and those of the two-peptide lantibiotic lacticin 3147, these two systems show similarities in their mode of action. Like Ltn alpha, Hal alpha binds to a target on the surface of Gram-positive bacteria, and like Ltn beta, the addition of Hal beta results In pore formation and potassium efflux. Using Hal alpha mutants, its B- and C-thioether rings are shown to be Important but not required for bioactivity. A similar observation was made with mutants of Glu22, a residue that Is highly conserved among several lipid II-binding lantibiotics such as mersacidin.