Insights into the Mechanism of Action of the Two-Peptide Lantibiotic Lacticin 3147.

Lacticin 3147 is a two peptide lantibiotc (LtnA1 and LtnA2) that displays nanomolar activity against many Gram-positive bacteria. Lacticin 3147 may exert its antimicrobial effect by several mechanisms. Isothermal titration calorimetry experiments show that only LtnA1 binds to the peptidoglycan precursor lipid II, which could inhibit peptidoglycan biosynthesis. An experimentally supported model of the resulting complex suggests that the key binding partners are the C-terminus of LtnA1 and pyrophosphate of lipid II. A combination of in vivo and in vitro assays indicates that LtnA1 and LtnA2 can induce rapid membrane lysis without the need for lipid II binding. However, the presence of lipid II substantially increases the activity of lacticin 3147. Furthermore, studies with synthetic LtnA2 analogues containing either desmethyl- or oxa-lanthionine rings confirm that the precise geometry of these rings is essential for this synergistic activity.

[1]  T. Zendo,et al.  LiaRS reporter assay: A simple tool to identify lipid II binding moieties in lantibiotic nukacin ISK-1. , 2017, Journal of bioscience and bioengineering.

[2]  J. Vederas,et al.  Antimicrobial lipopeptide tridecaptin A1 selectively binds to Gram-negative lipid II , 2016, Proceedings of the National Academy of Sciences.

[3]  Joel S. Freundlich,et al.  Discovery of MRSA active antibiotics using primary sequence from the human microbiome , 2016, Nature chemical biology.

[4]  M. Willmann,et al.  Human commensals producing a novel antibiotic impair pathogen colonization , 2016, Nature.

[5]  E. Breukink,et al.  Hit 'em where it hurts: The growing and structurally diverse family of peptides that target lipid-II. , 2016, Biochimica et biophysica acta.

[6]  O. Kuipers,et al.  Bacteriocins of lactic acid bacteria: extending the family , 2016, Applied Microbiology and Biotechnology.

[7]  E. Breukink,et al.  New Insights into Nisin's Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues. , 2016, Biochemistry.

[8]  J. Vederas,et al.  Synthesis of Tridecaptin-Antibiotic Conjugates with in Vivo Activity against Gram-Negative Bacteria. , 2015, Journal of medicinal chemistry.

[9]  C. Hill,et al.  Bioengineering Lantibiotics for Therapeutic Success , 2015, Front. Microbiol..

[10]  H. Sahl,et al.  Structural variations of the cell wall precursor lipid II in Gram-positive bacteria - Impact on binding and efficacy of antimicrobial peptides. , 2015, Biochimica et biophysica acta.

[11]  S. Donadio,et al.  Brominated Variant of the Lantibiotic NAI-107 with Enhanced Antibacterial Potency. , 2015, Journal of natural products.

[12]  Leif Smith,et al.  Multipronged approach for engineering novel peptide analogues of existing lantibiotics , 2015, Expert opinion on drug discovery.

[13]  E. Breukink,et al.  Semisynthetic Lipopeptides Derived from Nisin Display Antibacterial Activity and Lipid II Binding on Par with That of the Parent Compound. , 2015, Journal of the American Chemical Society.

[14]  R. Süssmuth,et al.  The gyrase inhibitor albicidin consists of p-aminobenzoic acids and cyanoalanine. , 2015, Nature chemical biology.

[15]  K. Lewis,et al.  A new antibiotic kills pathogens without detectable resistance , 2015, Nature.

[16]  K. Houk,et al.  Substrate Control in Stereoselective Lanthionine Biosynthesis , 2014, Nature chemistry.

[17]  J. Vederas,et al.  Unacylated tridecaptin A₁ acts as an effective sensitiser of Gram-negative bacteria to other antibiotics. , 2014, International journal of antimicrobial agents.

[18]  A. Tabor.  Recent advances in synthetic analogues of lantibiotics: What can we learn from these? , 2014, Bioorganic chemistry.

[19]  P. G. Arnison,et al.  Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. , 2013, Natural product reports.

[20]  W. A. van der Donk,et al.  Discovery, biosynthesis, and engineering of lantipeptides. , 2012, Annual review of biochemistry.

[21]  K. Bush.  Antimicrobial agents targeting bacterial cell walls and cell membranes. , 2012, Revue scientifique et technique.

[22]  D. Kohda,et al.  Ring A of nukacin ISK-1: a lipid II-binding motif for type-A(II) lantibiotic. , 2012, Journal of the American Chemical Society.

[23]  S. Walker,et al.  Haloduracin α Binds the Peptidoglycan Precursor Lipid II with 2:1 Stoichiometry , 2011, Journal of the American Chemical Society.

[24]  J. Vederas,et al.  Solid supported chemical syntheses of both components of the lantibiotic lacticin 3147. , 2011, Journal of the American Chemical Society.

[25]  T. Vernet,et al.  Identification of FtsW as a transporter of lipid-linked cell wall precursors across the membrane , 2011, The EMBO journal.

[26]  Søren Neve,et al.  Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall Precursor Lipid II , 2010, Science.

[27]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[28]  J. Vederas,et al.  Synthesis and biological activity of oxa-lacticin A2, a lantibiotic analogue with sulfur replaced by oxygen. , 2009, Organic letters.

[29]  W. A. van der Donk,et al.  Insights into the Mode of Action of the Two-Peptide Lantibiotic Haloduracin , 2009, ACS chemical biology.

[30]  H. Sahl,et al.  Influence of Ca2+ Ions on the Activity of Lantibiotics Containing a Mersacidin-Like Lipid II Binding Motif , 2009, Applied and Environmental Microbiology.

[31]  J. Vederas,et al.  Solid-supported synthesis and biological evaluation of the lantibiotic peptide bis(desmethyl) lacticin 3147 A2. , 2008, Angewandte Chemie.

[32]  H. Sahl,et al.  The lantibiotic mersacidin is a strong inducer of the cell wall stress response of Staphylococcus aureus , 2008, BMC Microbiology.

[33]  W. A. van der Donk,et al.  Structure-activity relationship studies of the two-component lantibiotic haloduracin. , 2008, Chemistry & biology.

[34]  K. Dunbar,et al.  Anion-pi interactions. , 2008, Chemical Society reviews.

[35]  E. Breukink,et al.  Expanding role of lipid II as a target for lantibiotics. , 2007, Future microbiology.

[36]  R. P. Ross,et al.  Identification of a novel two-peptide lantibiotic, haloduracin, produced by the alkaliphile Bacillus halodurans C-125. , 2007, FEMS microbiology letters.

[37]  Neil L. Kelleher,et al.  Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic , 2006, Proceedings of the National Academy of Sciences.

[38]  R. P. Ross,et al.  Complete alanine scanning of the two‐component lantibiotic lacticin 3147: generating a blueprint for rational drug design , 2006, Molecular microbiology.

[39]  H. Sahl,et al.  The mode of action of the lantibiotic lacticin 3147 – a complex mechanism involving specific interaction of two peptides and the cell wall precursor lipid II , 2006, Molecular microbiology.

[40]  R. P. Ross,et al.  Sequential Actions of the Two Component Peptides of the Lantibiotic Lacticin 3147 Explain Its Antimicrobial Activity at Nanomolar Concentrations , 2005, Antimicrobial Agents and Chemotherapy.

[41]  R. Kaptein,et al.  The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics , 2004, Nature Structural &Molecular Biology.

[42]  B. de Kruijff,et al.  Assembly and stability of nisin-lipid II pores. , 2004, Biochemistry.

[43]  J. Vederas,et al.  Structural characterization of lacticin 3147, a two-peptide lantibiotic with synergistic activity. , 2004, Biochemistry.

[44]  A. Heck,et al.  Lipid II Is an Intrinsic Component of the Pore Induced by Nisin in Bacterial Membranes* , 2003, Journal of Biological Chemistry.

[45]  R. Kaptein,et al.  NMR Study of Mersacidin and Lipid II Interaction in Dodecylphosphocholine Micelles , 2003, The Journal of Biological Chemistry.

[46]  R. P. Ross,et al.  Lantibiotics: structure, biosynthesis and mode of action. , 2001, FEMS microbiology reviews.

[47]  Oscar P. Kuipers,et al.  Specific Binding of Nisin to the Peptidoglycan Precursor Lipid II Combines Pore Formation and Inhibition of Cell Wall Biosynthesis for Potent Antibiotic Activity* , 2001, The Journal of Biological Chemistry.

[48]  H. Sahl,et al.  Extensive Post-translational Modification, Including Serine to d-Alanine Conversion, in the Two-component Lantibiotic, Lacticin 3147* , 1999, The Journal of Biological Chemistry.

[49]  O. Kuipers,et al.  Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic. , 1999, Science.

[50]  H. Sahl,et al.  The Lantibiotic Mersacidin Inhibits Peptidoglycan Synthesis by Targeting Lipid II , 1998, Antimicrobial Agents and Chemotherapy.

[51]  K. Wüthrich,et al.  Torsion angle dynamics for NMR structure calculation with the new program DYANA. , 1997, Journal of molecular biology.

[52]  H. Sahl,et al.  The lantibiotic mersacidin inhibits peptidoglycan biosynthesis at the level of transglycosylation. , 1997, European journal of biochemistry.

[53]  S. Langsrud,et al.  Flow cytometry for rapid assessment of viability after exposure to a quaternary ammonium compound. , 1996, The Journal of applied bacteriology.

[54]  R. P. Ross,et al.  An application in cheddar cheese manufacture for a strain of Lactococcus lactis producing a novel broad-spectrum bacteriocin, lacticin 3147 , 1996, Applied and environmental microbiology.

[55]  R. Wenzel,et al.  In vitro activity of mersacidin (M87-1551), an investigational peptide antibiotic tested against gram-positive bloodstream isolates. , 1992, Diagnostic microbiology and infectious disease.

[56]  D. Molenaar,et al.  Continuous measurement of the cytoplasmic pH in Lactococcus lactis with a fluorescent pH indicator. , 1991, Biochimica et biophysica acta.

[57]  M. Vaara,et al.  Sensitization of Gram-negative bacteria to antibiotics and complement by a nontoxic oligopeptide , 1983, Nature.

[58]  H. Perkins.  Specificity of combination between mucopeptide precursors and vancomycin or ristocetin. , 1969, The Biochemical journal.