Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.

Autor:	Blaskovich MAT; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia. m.blaskovich@uq.edu.au., Hansford KA; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Gong Y; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Butler MS; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Muldoon C; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Huang JX; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Ramu S; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Silva AB; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia.; AC Immune SA, EPFL Innovation Park, CH-1015, Lausanne, Switzerland., Cheng M; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Kavanagh AM; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Ziora Z; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Premraj R; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Lindahl F; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Bradford TA; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Lee JC; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Karoli T; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia.; Novasep (Dynamit Nobel Explosivstoff und Systemtechnik), Kalkstrasse 218, 51377, Leverkusen, Germany., Pelingon R; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Edwards DJ; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Amado M; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Elliott AG; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Phetsang W; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Daud NH; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Deecke JE; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Sidjabat HE; UQ Centre for Clinical Research, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, QLD, 4029, Australia., Ramaologa S; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Zuegg J; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia., Betley JR; AdProTech Ltd, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK.; Illumina Cambridge Ltd, Capital Park, Fulbourn, Cambridge, CB21 5XE, UK., Beevers APG; AdProTech Ltd, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK.; Sterling Pharma Solutions, Sterling Place, Dudley, Cramlington, Northumberland, NE23 7QG, UK., Smith RAG; AdProTech Ltd, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK.; School of Immunology and Microbial Science, Kings College London, Guy's Hospital, London, SE1 9RT, UK., Roberts JA; UQ Centre for Clinical Research, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, QLD, 4029, Australia.; School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia., Paterson DL; UQ Centre for Clinical Research, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, QLD, 4029, Australia., Cooper MA; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia. m.cooper@uq.edu.au.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Jan 02; Vol. 9 (1), pp. 22. Date of Electronic Publication: 2018 Jan 02.
DOI:	10.1038/s41467-017-02123-w
Abstrakt:	The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.
Databáze:	MEDLINE
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