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

Mark A. T. Blaskovich (), Karl A. Hansford, Yujing Gong, Mark S. Butler, Craig Muldoon, Johnny X. Huang, Soumya Ramu, Alberto B. Silva, Mu Cheng, Angela M. Kavanagh, Zyta Ziora, Rajaratnam Premraj, Fredrik Lindahl, Tanya A. Bradford, June C. Lee, Tomislav Karoli, Ruby Pelingon, David J. Edwards, Maite Amado, Alysha G. Elliott, Wanida Phetsang, Noor Huda Daud, Johan E. Deecke, Hanna E. Sidjabat, Sefetogi Ramaologa, Johannes Zuegg, Jason R. Betley, Andrew P. G. Beevers, Richard A. G. Smith, Jason A. Roberts, David L. Paterson and Matthew A. Cooper ()
Additional contact information
Mark A. T. Blaskovich: The University of Queensland
Karl A. Hansford: The University of Queensland
Yujing Gong: The University of Queensland
Mark S. Butler: The University of Queensland
Craig Muldoon: The University of Queensland
Johnny X. Huang: The University of Queensland
Soumya Ramu: The University of Queensland
Alberto B. Silva: The University of Queensland
Mu Cheng: The University of Queensland
Angela M. Kavanagh: The University of Queensland
Zyta Ziora: The University of Queensland
Rajaratnam Premraj: The University of Queensland
Fredrik Lindahl: The University of Queensland
Tanya A. Bradford: The University of Queensland
June C. Lee: The University of Queensland
Tomislav Karoli: The University of Queensland
Ruby Pelingon: The University of Queensland
David J. Edwards: The University of Queensland
Maite Amado: The University of Queensland
Alysha G. Elliott: The University of Queensland
Wanida Phetsang: The University of Queensland
Noor Huda Daud: The University of Queensland
Johan E. Deecke: The University of Queensland
Hanna E. Sidjabat: The University of Queensland, Royal Brisbane and Women’s Hospital Campus
Sefetogi Ramaologa: The University of Queensland
Johannes Zuegg: The University of Queensland
Jason R. Betley: AdProTech Ltd, Chesterford Research Park
Andrew P. G. Beevers: AdProTech Ltd, Chesterford Research Park
Richard A. G. Smith: AdProTech Ltd, Chesterford Research Park
Jason A. Roberts: The University of Queensland, Royal Brisbane and Women’s Hospital Campus
David L. Paterson: The University of Queensland, Royal Brisbane and Women’s Hospital Campus
Matthew A. Cooper: The University of Queensland

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02123-w

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