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

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 prot...

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Bibliographic Details
Published in:	Nature communications Vol. 9; no. 1; pp. 22 - 17
Main Authors:	Blaskovich, Mark A. T., Hansford, Karl A., Gong, Yujing, Butler, Mark S., Muldoon, Craig, Huang, Johnny X., Ramu, Soumya, Silva, Alberto B., Cheng, Mu, Kavanagh, Angela M., Ziora, Zyta, Premraj, Rajaratnam, Lindahl, Fredrik, Bradford, Tanya A., Lee, June C., Karoli, Tomislav, Pelingon, Ruby, Edwards, David J., Amado, Maite, Elliott, Alysha G., Phetsang, Wanida, Daud, Noor Huda, Deecke, Johan E., Sidjabat, Hanna E., Ramaologa, Sefetogi, Zuegg, Johannes, Betley, Jason R., Beevers, Andrew P. G., Smith, Richard A. G., Roberts, Jason A., Paterson, David L., Cooper, Matthew A.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-01-2018 Nature Publishing Group Nature Portfolio
Subjects:	631/154/309/2144 631/326/22/1290 631/92/609 692/699/255/1318 Animals Anti-Bacterial Agents - metabolism Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - pharmacology Antibiotics Bacteria Bacteria - classification Bacteria - drug effects Bacterial infections Cell Survival - drug effects Daptomycin Daptomycin - pharmacology Drug development Drug resistance Drug Resistance, Bacterial - drug effects Drugs Exploitation Glycopeptides - metabolism Gram-positive bacteria Health risks HEK293 Cells Hep G2 Cells Humanities and Social Sciences Humans Intravenous administration Lipid composition Lipophilic Male Membrane Proteins - metabolism Membranes Methicillin Methicillin-Resistant Staphylococcus aureus - drug effects Mice Microbial Sensitivity Tests Microbial Viability - drug effects multidisciplinary Peptide libraries Proteins Public health Receptors Regeneration Science Science (multidisciplinary) Staphylococcus aureus Staphylococcus aureus - drug effects Staphylococcus infections Vancomycin Vancomycin - pharmacology
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Summary:	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. The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-017-02123-w