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Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum

Nature Nanotechnology volume 9, pages 225–232 (2014)Cite this article

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Abstract

There is a growing appreciation that mechanical signals can be as important as chemical and electrical signals in biology. To include such signals in a systems biology description for understanding pathobiology and developing therapies, quantitative experiments on how solution-phase and surface chemistry together produce biologically relevant mechanical signals are needed. Because of the appearance of drug-resistant hospital ‘superbugs’, there is currently great interest in the destruction of bacteria by bound drug–target complexes that stress bacterial cell membranes. Here, we use nanomechanical cantilevers as surface-stress sensors, together with equilibrium theory, to describe quantitatively the mechanical response of a surface receptor to different antibiotics in the presence of competing ligands in solution. The antibiotics examined are the standard, Food and Drug Administration-approved drug of last resort, vancomycin, and the yet-to-be approved oritavancin, which shows promise for controlling vancomycin-resistant infections. The work reveals variations among strong and weak competing ligands, such as proteins in human serum, that determine dosages in drug therapies. The findings further enhance our understanding of the biophysical mode of action of the antibiotics and will help develop better treatments, including choice of drugs as well as dosages, against pathogens.

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Figure 1: Exploiting the nanomechanics of drug–target interactions to investigate the impact of dosing and competing ligands on the functionality of drug molecules.
Figure 2: Nanomechanics of drug–target interactions in the presence of weak competing ligands at clinically relevant concentrations.
Figure 3: Nanomechanics of drug–target interactions in the presence of strong competing ligands at clinically relevant concentrations.
Figure 4: Investigating the mechanics of drug–target interactions using cantilever sensor arrays.
Figure 5: Nanomechanical quantitation of drug–target interactions in whole blood serum at clinically relevant concentrations.

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Acknowledgements

The authors acknowledge support, funding and materials from the EPSRC Interdisciplinary Research Centre in Nanotechnology (Cambridge, UCL, Bristol, GR/R45680/01), the Royal Society (RS), Bio Nano Consulting (BNC), Targanta Therapeutics, EPSRC Speculative Engineering Program (EP/D505925/1), the European Union FP7 Project VSMMART Nano (managed by BNC), EPSRC Grand Challenge in Nanotechnology for Healthcare (EP/G062064/1) and the EPSRC IRC in Early Warning Sensing Systems for Infectious Diseases (EP/K031953/1). M.A.C. acknowledges support from NHMRC Australia Fellowship AF511105. The authors thank S. B. Patil, G. T. Charras and I. K. Robinson for discussions.

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Authors and Affiliations

  1. Division of Medicine and Department of Physics and Astronomy, London Centre for Nanotechnology, University College London, 17–19 Gordon Street, London, WC1H 0AH, UK

    Joseph W. Ndieyira, Natascha Kappeler, Stephen Logan, Rachel A. McKendry & Gabriel Aeppli

  2. Department of Chemistry, Jomo Kenyatta University of Agriculture and Technology, PO Box 62000, Nairobi, Kenya

    Joseph W. Ndieyira

  3. Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, St Lucia, 4072, Brisbane, Australia

    Matthew A. Cooper

  4. Department of Chemistry, Lensfield Road, University of Cambridge, Cambridge, CB2 1EW, UK

    Chris Abell

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Contributions

J.W.N., R.A.M. and G.A. conceived and designed the experiments. J.W.N. and G.A. formulated the mathematical models to quantify the transduction between chemical and mechanical signals to uncover the role of strong and weak competing ligands in the functionality of drugs and to show quantitatively how surface binding affinity is correlated with competing solution phase processes. J.W.N. performed the experiments and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Joseph W. Ndieyira or Rachel A. McKendry.

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Competing interests

Research was partially funded by Targanta via Bio-Nano Consulting and Targanta had a financial interest in the commercial success of Oritavancin. G.A. is co-author of two patents (US2010/0149545 and EP2156441 A1: G. Aeppli and B. Dueck: “Apparatus and Methods for measuring deformation of a cantilever using interferometry”, publication 24th Feb 2010 and WO 2013144646 A3: R. Hermans and G. Aeppli: “Measuring Surface Curvature”, publication 21st November 2013) whose value could increase if the methods and ideas described in this paper find widespread application.

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Ndieyira, J., Kappeler, N., Logan, S. et al. Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum. Nature Nanotech 9, 225–232 (2014). https://doi.org/10.1038/nnano.2014.33

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