Nanomechanical detection of antibiotic–mucopeptide binding in a model for superbug drug resistance

Abstract

The alarming growth of the antibiotic-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. We report the label-free detection of vancomycin binding to bacterial cell wall precursor analogues (mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically relevant concentrations in blood serum. Differential measurements have quantified binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide analogues. Moreover, by systematically modifying the mucopeptide density we gain new insights into the origin of surface stress. We propose that stress is a product of a local chemical binding factor and a geometrical factor describing the mechanical connectivity of regions activated by local binding in terms of a percolation process. Our findings place BioMEMS devices in a new class of percolative systems. The percolation concept will underpin the design of devices and coatings to significantly lower the drug detection limit and may also have an impact on our understanding of antibiotic drug action in bacteria.

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Figure 1: The nanomechanical detection of vancomycin–mucopeptide analogue interactions on multiple cantilever arrays.
Figure 2: Investigation of the specificity and sensitivity of antibiotic–mucopeptide interactions on cantilever arrays.
Figure 3: Nanomechanical detection of antibiotics in blood serum at clinically relevant concentrations.
Figure 4: Nanomechanical drug–target percolation on cantilever arrays.
Figure 5: Concepts underpinning nanomechanical antibiotic transduction.

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Acknowledgements

We acknowledge funding from the Engineering and Physical Sciences Research Council (Speculative Engineering funding programme, J.W.N, R.McK., G.A., M.W., D.Z.), Interdisciplinary Research Centre in Nanotechnology (Cambridge, UCL and Bristol, M.W., J.W.N., R.McK.), the Royal Society (R.McK., J.W.N.), Biotechnology and Biological Science Research Council (R.McK.), the Wolfson Foundation (G.A.) and Cancer Research UK (A.D.B.). We thank E. Smith (University of Nottingham EPSRC XPS Open Access scheme) and J. and R. Galbraith (UCL Statistics) for helpful discussions.

Author information

J.W.N. and M.W. contributed equally to this manuscript. All authors discussed the results and commented on the manuscript.

Correspondence to Rachel A. McKendry.

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Ndieyira, J., Watari, M., Barrera, A. et al. Nanomechanical detection of antibiotic–mucopeptide binding in a model for superbug drug resistance. Nature Nanotech 3, 691–696 (2008). https://doi.org/10.1038/nnano.2008.275

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