Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 328 (5982): 1168-1172

Copyright © 2010 by the American Association for the Advancement of Science

Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall Precursor Lipid II

Tanja Schneider,1 Thomas Kruse,2 Reinhard Wimmer,3 Imke Wiedemann,1 Vera Sass,1 Ulrike Pag,1 Andrea Jansen,1 Allan K. Nielsen,4 Per H. Mygind,4 Dorotea S. Raventós,4 Søren Neve,4 Birthe Ravn,4 Alexandre M. J. J. Bonvin,5 Leonardo De Maria,4 Anders S. Andersen,2,4 Lora K. Gammelgaard,4 Hans-Georg Sahl,1 Hans-Henrik Kristensen4,*

Abstract: Host defense peptides such as defensins are components of innate immunity and have retained antibiotic activity throughout evolution. Their activity is thought to be due to amphipathic structures, which enable binding and disruption of microbial cytoplasmic membranes. Contrary to this, we show that plectasin, a fungal defensin, acts by directly binding the bacterial cell-wall precursor Lipid II. A wide range of genetic and biochemical approaches identify cell-wall biosynthesis as the pathway targeted by plectasin. In vitro assays for cell-wall synthesis identified Lipid II as the specific cellular target. Consistently, binding studies confirmed the formation of an equimolar stoichiometric complex between Lipid II and plectasin. Furthermore, key residues in plectasin involved in complex formation were identified using nuclear magnetic resonance spectroscopy and computational modeling.

1 Pharmaceutical Microbiology Section, Institute for Medical Microbiology, Immunology, and Parasitology, University of Bonn, D-53115 Bonn, Germany.
2 Statens Serum Institut, 2300 Copenhagen S, Denmark.
3 Department of Biotechnology, Chemistry, and Environmental Engineering, Aalborg University, DK-9000 Aalborg, Denmark.
4 Novozymes AS, DK-2880 Bagsvaerd, Denmark.
5 Department of Chemistry, Faculty of Science, Utrecht University, 3584 CH Utrecht, Netherlands.

* To whom correspondence should be addressed. E-mail: hahk{at}novozymes.com

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Small cationic antimicrobial peptides delocalize peripheral membrane proteins.
M. Wenzel, A. I. Chiriac, A. Otto, D. Zweytick, C. May, C. Schumacher, R. Gust, H. B. Albada, M. Penkova, U. Kramer, et al. (2014)
PNAS 111, E1409-E1418
   Abstract »    Full Text »    PDF »
Restoration of Bioactive Lantibiotic Suicin from a Remnant lan Locus of Pathogenic Streptococcus suis Serotype 2.
J. Wang, Y. Gao, K. Teng, J. Zhang, S. Sun, and J. Zhong (2014)
Appl. Envir. Microbiol. 80, 1062-1071
   Abstract »    Full Text »    PDF »
Phosphoinositide-mediated oligomerization of a defensin induces cell lysis.
I. K. Poon, A. A. Baxter, F. T. Lay, G. D. Mills, C. G. Adda, J. A. Payne, T. K. Phan, G. F. Ryan, J. A. White, P. K. Veneer, et al. (2014)
eLife Sci 3, e01808
   Abstract »    Full Text »    PDF »
Microbicidal effects of {alpha}- and {theta}-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa.
K. P. Tai, K. Kamdar, J. Yamaki, V. V. Le, D. Tran, P. Tran, M. E. Selsted, A. J. Ouellette, and A. Wong-Beringer (2013)
Innate Immunity
   Abstract »    Full Text »    PDF »
A de novo-designed antimicrobial peptide with activity against multiresistant Staphylococcus aureus acting on RsbW kinase.
A. Dangel, N. Ackermann, O. Abdel-Hadi, R. Maier, K. Onder, P. Francois, C. W. Muller, J. Pane-Farre, S. Engelmann, J. Schrenzel, et al. (2013)
FASEB J 27, 4476-4488
   Abstract »    Full Text »    PDF »
Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma Identifies CDK4 and IGF1R as Synergistic Drug Targets.
M. L. Miller, E. J. Molinelli, J. S. Nair, T. Sheikh, R. Samy, X. Jing, Q. He, A. Korkut, A. M. Crago, S. Singer, et al. (2013)
Science Signaling 6, ra85
   Abstract »    Full Text »    PDF »
Targeting Mycobacterium tuberculosis and Other Microbial Pathogens Using Improved Synthetic Antibacterial Peptides.
S. Ramon-Garcia, R. Mikut, C. Ng, S. Ruden, R. Volkmer, M. Reischl, K. Hilpert, and C. J. Thompson (2013)
Antimicrob. Agents Chemother. 57, 2295-2303
   Abstract »    Full Text »    PDF »
Eurocin, a New Fungal Defensin: STRUCTURE, LIPID BINDING, AND ITS MODE OF ACTION.
J. S. Oeemig, C. Lynggaard, D. H. Knudsen, F. T. Hansen, K. D. Norgaard, T. Schneider, B. S. Vad, D. H. Sandvang, L. A. Nielsen, S. Neve, et al. (2012)
J. Biol. Chem. 287, 42361-42372
   Abstract »    Full Text »    PDF »
Proteomic Response of Bacillus subtilis to Lantibiotics Reflects Differences in Interaction with the Cytoplasmic Membrane.
M. Wenzel, B. Kohl, D. Munch, N. Raatschen, H. B. Albada, L. Hamoen, N. Metzler-Nolte, H.-G. Sahl, and J. E. Bandow (2012)
Antimicrob. Agents Chemother. 56, 5749-5757
   Abstract »    Full Text »    PDF »
Cell Envelope Stress Response in Cell Wall-Deficient L-Forms of Bacillus subtilis.
D. Wolf, P. Dominguez-Cuevas, R. A. Daniel, and T. Mascher (2012)
Antimicrob. Agents Chemother. 56, 5907-5915
   Abstract »    Full Text »    PDF »
Progressive Structuring of a Branched Antimicrobial Peptide on the Path to the Inner Membrane Target.
Y. Bai, S. Liu, J. Li, R. Lakshminarayanan, P. Sarawathi, C. Tang, D. Ho, C. Verma, R. W. Beuerman, and K. Pervushin (2012)
J. Biol. Chem. 287, 26606-26617
   Abstract »    Full Text »    PDF »
Functional Determinants of Human Enteric {alpha}-Defensin HD5: CRUCIAL ROLE FOR HYDROPHOBICITY AT DIMER INTERFACE.
M. Rajabi, B. Ericksen, X. Wu, E. de Leeuw, L. Zhao, M. Pazgier, and W. Lu (2012)
J. Biol. Chem. 287, 21615-21627
   Abstract »    Full Text »    PDF »
Lipodepsipeptide Empedopeptin Inhibits Cell Wall Biosynthesis through Ca2+-dependent Complex Formation with Peptidoglycan Precursors.
A. Muller, D. Munch, Y. Schmidt, K. Reder-Christ, G. Schiffer, G. Bendas, H. Gross, H.-G. Sahl, T. Schneider, and H. Brotz-Oesterhelt (2012)
J. Biol. Chem. 287, 20270-20280
   Abstract »    Full Text »    PDF »
Dermatophytic defensin with antiinfective potential.
S. Zhu, B. Gao, P. J. Harvey, and D. J. Craik (2012)
PNAS 109, 8495-8500
   Abstract »    Full Text »    PDF »
Alternative Luminal Activation Mechanisms for Paneth Cell {alpha}-Defensins.
J. R. Mastroianni, J. K. Costales, J. Zaksheske, M. E. Selsted, N. H. Salzman, and A. J. Ouellette (2012)
J. Biol. Chem. 287, 11205-11212
   Abstract »    Full Text »    PDF »
Sometimes It Takes Two to Tango: CONTRIBUTIONS OF DIMERIZATION TO FUNCTIONS OF HUMAN {alpha}-DEFENSIN HNP1 PEPTIDE.
M. Pazgier, G. Wei, B. Ericksen, G. Jung, Z. Wu, E. de Leeuw, W. Yuan, H. Szmacinski, W.-Y. Lu, J. Lubkowski, et al. (2012)
J. Biol. Chem. 287, 8944-8953
   Abstract »    Full Text »    PDF »
Exometabolome Analysis Identifies Pyruvate Dehydrogenase as a Target for the Antibiotic Triphenylbismuthdichloride in Multiresistant Bacterial Pathogens.
T. Birkenstock, M. Liebeke, V. Winstel, B. Krismer, C. Gekeler, M. J. Niemiec, H. Bisswanger, M. Lalk, and A. Peschel (2012)
J. Biol. Chem. 287, 2887-2895
   Abstract »    Full Text »    PDF »
Bacterial-Fungal Interactions: Hyphens between Agricultural, Clinical, Environmental, and Food Microbiologists.
P. Frey-Klett, P. Burlinson, A. Deveau, M. Barret, M. Tarkka, and A. Sarniguet (2011)
Microbiol. Mol. Biol. Rev. 75, 583-609
   Abstract »    Full Text »    PDF »
Antibiotic research in the age of omics: from expression profiles to interspecies communication.
T. Wecke and T. Mascher (2011)
J. Antimicrob. Chemother. 66, 2689-2704
   Abstract »    Full Text »    PDF »
Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus.
Y. Q. Xiong, W. A. Hady, A. Deslandes, A. Rey, L. Fraisse, H.-H. Kristensen, M. R. Yeaman, and A. S. Bayer (2011)
Antimicrob. Agents Chemother. 55, 5325-5330
   Abstract »    Full Text »    PDF »
A Mig-14-like protein (PA5003) affects antimicrobial peptide recognition in Pseudomonas aeruginosa.
N. Jochumsen, Y. Liu, S. Molin, and A. Folkesson (2011)
Microbiology 157, 2647-2657
   Abstract »    Full Text »    PDF »
Mechanism of Action and Limited Cross-Resistance of New Lipopeptide MX-2401.
E. Rubinchik, T. Schneider, M. Elliott, W. R. P. Scott, J. Pan, C. Anklin, H. Yang, D. Dugourd, A. Muller, K. Gries, et al. (2011)
Antimicrob. Agents Chemother. 55, 2743-2754
   Abstract »    Full Text »    PDF »
Resistance and Tolerance to Tropodithietic Acid, an Antimicrobial in Aquaculture, Is Hard To Select.
C. H. Porsby, M. A. Webber, K. F. Nielsen, L. J. V. Piddock, and L. Gram (2011)
Antimicrob. Agents Chemother. 55, 1332-1337
   Abstract »    Full Text »    PDF »
Peptide Antibiotic Sensing and Detoxification Modules of Bacillus subtilis.
A. Staron, D. E. Finkeisen, and T. Mascher (2011)
Antimicrob. Agents Chemother. 55, 515-525
   Abstract »    Full Text »    PDF »
Challenges of Antibacterial Discovery.
L. L. Silver (2011)
Clin. Microbiol. Rev. 24, 71-109
   Abstract »    Full Text »    PDF »
Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold.
B. Findlay, G. G. Zhanel, and F. Schweizer (2010)
Antimicrob. Agents Chemother. 54, 4049-4058
   Abstract »    Full Text »    PDF »
Insight into Invertebrate Defensin Mechanism of Action: OYSTER DEFENSINS INHIBIT PEPTIDOGLYCAN BIOSYNTHESIS BY BINDING TO LIPID II.
P. Schmitt, M. Wilmes, M. Pugniere, A. Aumelas, E. Bachere, H.-G. Sahl, T. Schneider, and D. Destoumieux-Garzon (2010)
J. Biol. Chem. 285, 29208-29216
   Abstract »    Full Text »    PDF »
Intracellular activity of the peptide antibiotic NZ2114: studies with Staphylococcus aureus and human THP-1 monocytes, and comparison with daptomycin and vancomycin.
K. S. Brinch, P. M. Tulkens, F. Van Bambeke, N. Frimodt-Moller, N. Hoiby, and H.-H. Kristensen (2010)
J. Antimicrob. Chemother. 65, 1720-1724
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882