title: Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum.
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.
authors.affiliation: 1] London Centre for Nanotechnology, Division of Medicine and Department of Physics and Astronomy, University College London, 17-19 Gordon Street, London WC1H 0AH, UK [2] Jomo Kenyatta University of Agriculture and Technology, Department of Chemistry, PO Box 62000, Nairobi, Kenya.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Ndieyira
authors.affiliation: London Centre for Nanotechnology, Division of Medicine and Department of Physics and Astronomy, University College London, 17-19 Gordon Street, London WC1H 0AH, UK.
authors.forename: Natascha
authors.initials: N
authors.lastname: Kappeler
authors.affiliation: London Centre for Nanotechnology, Division of Medicine and Department of Physics and Astronomy, University College London, 17-19 Gordon Street, London WC1H 0AH, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Logan
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, St Lucia, Brisbane 4072, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
authors.affiliation: London Centre for Nanotechnology, Division of Medicine and Department of Physics and Astronomy, University College London, 17-19 Gordon Street, London WC1H 0AH, UK.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: McKendry
authors.affiliation: London Centre for Nanotechnology, Division of Medicine and Department of Physics and Astronomy, University College London, 17-19 Gordon Street, London WC1H 0AH, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Aeppli
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism; D001696:Biomechanical Phenomena; D015374:Biosensing Techniques / Q000295:instrumentation; D004867:Equipment Design; D006020:Glycopeptides / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D000077427:Lipoglycopeptides; D008954:Models, Biological; D036103:Nanotechnology / Q000295:instrumentation*; D012997:Solvents / Q000378:metabolism; D013499:Surface Properties; D014640:Vancomycin / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D008024:Ligands; D000077427:Lipoglycopeptides; D012997:Solvents; D014640:Vancomycin; C100708:oritavancin