Bibacillin 1: A two-component lantibiotic from Bacillus thuringiensis

Here we describe bibacillin 1 - a two-component lantibiotic from Bacillus thuringiensis. The peptides that comprise bibacillin 1 are modified by a class II lanthipeptide synthetase Bib1M producing two peptides with non-overlapping ring patterns that are reminiscent of cerecidin and the short component of the enterococcal cytolysin (CylL_S"), a virulence factor associated with human disease. Stereochemical analysis demonstrated that each component contains LL-methyllanthionine and DL-lanthionine. The mature bibacillin 1 peptides showed cooperative bactericidal activity against Gram-positive bacteria, including members of ESKAPE pathogens, and weak hemolytic activity. Optimal ratio studies suggest that bibacillin 1 works best when the components are present in a 1:1 ratio, but near optimal activity was observed at ratios strongly favouring one component over the other, suggesting that the two peptides may have different but complementary targets. Mechanism of action studies suggest a lipid II-independent killing action distinguishing bibacillin 1 from two other two-component lantibiotics haloduracin and lacticin 3147. One of the two components of bibacillin 1 showed cross reactivity with the cytolysin regulatory system. These result support the involvement of bibacillin 1 in quorum sensing and raise questions about the impact of CylL_S"-like natural products on lanthipeptide expression in diverse bacterial communities.