title: Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Knerr
authors.forename: Trent J
authors.initials: TJ
authors.lastname: Oman
authors.forename: Chantal V
authors.initials: CV
authors.lastname: Garcia De Gonzalo
authors.forename: Tania J
authors.initials: TJ
authors.lastname: Lupoli
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000166:cytology / Q000187:drug effects; D001430:Bacteriocins / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy; D029968:Escherichia coli Proteins / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D013294:Lactococcus lactis / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D008969:Molecular Sequence Data; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism*; D046928:Peptidoglycan Glycosyltransferase / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D029968:Escherichia coli Proteins; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; C082508:lacticin 481; D046928:Peptidoglycan Glycosyltransferase; C478681:penicillin-binding protein 1B, E coli; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase