lacticin-481 and Escherichia-coli-Infections

Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain the thioether structures lanthionine and methyllanthionine and exert potent antimicrobial activity against Gram-positive bacteria. At present, detailed modes-of-action are only known for a small subset of family members. Lacticin 481, a tricyclic lantibiotic, contains a lipid II binding motif present in related compounds such as mersacidin and nukacin ISK-1. Here, we show that lacticin 481 inhibits PBP1b-catalyzed peptidoglycan formation. Furthermore, we show that changes in potency of analogues of lacticin 481 containing non-proteinogenic amino acids correlate positively with the potency of inhibition of the transglycosylase activity of PBP1b. Thus, lipid II is the likely target of lacticin 481, and use of non-proteinogenic amino acids resulted in stronger inhibition of the target. Additionally, we demonstrate that lacticin 481 does not form pores in the membranes of susceptible bacteria, a common mode-of-action of other lantibiotics.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Bacillus subtilis; Bacteriocins; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Glycosylation; Humans; Lactococcus lactis; Molecular Sequence Data; Penicillin-Binding Proteins; Peptidoglycan; Peptidoglycan Glycosyltransferase; Permeability; Serine-Type D-Ala-D-Ala Carboxypeptidase