Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin

The lantibiotic haloduracin consists of two post-translationally processed peptides, Halm and Halo, 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 Hal alpha B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin's 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 Hal alpha-Ser26 and Hal beta-Ser22 escape dehydration, requiring revision of the Halo structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Hal alpha cystine that is dispensable for bioactivity protects Hal alpha from further proteolytic degradation.