Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin Original Research Article

The lantibiotic haloduracin consists of two posttranslationally processed peptides, Halα and Halβ, which act in synergy to provide bactericidal activity. An in vitro haloduracin production system was used to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Halα B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracinʹs predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine completely abolished antibacterial activity. This study also established that Halα-Ser26 and Halβ-Ser22 escape dehydration, requiring revision of the Halβ structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Halα cystine that is dispensable for bioactivity protects Halα from further proteolytic degradation.