Insights into the Biosynthesis of the Lantibiotic Mutacin 1140

The rise of antibiotic-resistant bacteria poses a large problem for healthcare systems across the world. This problem is further exacerbated by the lack of development in new types of antibiotics. The CDC has identified antibiotic development as one of the key solutions in combating antibiotic resistance. Lantibiotics, a class of posttranslationally modified (PTM) peptide antibiotics, are promising candidates for antibiotic development. Lantibiotics are characterized by the presence of lanthionine rings and dehydrated residues. Mutacin 1140, produced by Streptococcus mutans JH1140, is a lantibiotic which has shown promising activity against a variety of Gram-positive pathogens. Although lantibiotics, such as mutacin 1140 show promise, they are still hampered by the lack of development. Furthering the understanding of lantibiotic biosynthesis is crucial for promoting the development of lantibiotics. Lantibiotic biosynthesis requires a leader peptide for efficient posttranslational modification, which is then cleaved off to produce the full lantibiotic. A novel four amino acid EDLF motif was found to be important for biosynthesis in Mutacin 1140. Additionally, I have shown that a second cleavage occurs 8 amino acids upstream of the defined MutP cleavage site, and that this cleavage event is dependent upon position and not sequence. I sought to determine the importance of different PTM’s in the formation for the coordination of PTMs and transport of mutacin 1140. Deletion of the lanthionine rings show that lanthionine ring formation affects other PTM’s, and that it is important for transport out of the cytoplasm. The role of the unique S-[(Z)-2-aminovinyl]-D-cysteine (AviCys) residue found in mutacin 1140 is poorly understood. Removal of the C-terminal carboxyl group increases the antibiotic's affinity to its molecular target lipid II. A carboxyl variant of mutacin 1140 does not affect the other PTM’s and is important for activity. This variant is agreeable to the chemical addition of a wide variety of substrates, producing novel variants of mutacin 1140 with restored activity class of lantibiotics that can be screened for improvements in drug development. The advancements made in understanding the mutacin 1140 biosynthesis pathway will help in developing mutacin 1140 as a tool to help combat the problem of antibiotic resistance