Design of Next-Generation Antibiotics with cutting-edge NMR studies
Starting in 2020
Group and collaboration
Markus Weingarth PhD, NMR Spectroscopy, Bijvoet Centre for Biomolecular Research, Utrecht University
Eefjan Breukink PhD, Membrane Biochemistry & Biophysics, Bijvoet Centre for Biomolecular Research, Utrecht University
Tom Wennekes PhD, Chemical Glycobiology, Department of Chemical Biology & Drug Discovery, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University
PhD student: -
The dramatic rise of multi-drug resistant bacteria urgently calls for the development of novel antibiotics that target unexploited pathways. This PhD-project focuses on a fungal peptide called plectasin. Plectasin shows high activity against drug resistant bacteria and maintains its activity in rodent models. Yet, the available data fail to explain why the infamous MRSA is resistant to plectasin, while some plectasin analogues show high activity. Using cutting-edge solid-state NMR methods in native lipid membranes and other biophysical methods, we have recently acquired a large and compelling set of data. “Based on our novel insights and methodological edge, we propose two interrelated programmes aiming to gain a fundamental structural understanding of MRSA resistance to plectasin and to use this knowledge to break MRSA resistance and design even more powerful plectasin analogues."
Tasks / deliverables
- Solid-state NMR structure and dynamics of the NZ2114---Gly5-Lipid II complex in MRSA cell membranes.
- At least two plectasin variants with activities that are higher than NZ2114 towards Staphylococci.
- At least one lipidated plectasin variant with overall markedly increased antibiotic activity.