This week Nature Nanotechnology journal (October 12th) reveals how scientists from the London Centre for Nanotechnology (LCN) at UCL are using a novel nanomechanical approach to investigate the workings of vancomycin, one of the few antibiotics that can be used to combat increasingly resistant infections such as MRSA. The researchers, led by Dr Rachel McKendry and Professor Gabriel Aeppli, developed ultra-sensitive probes capable of providing new insight into how antibiotics work, paving the way for the development of more effective new drugs.
During the study Dr McKendry, Joseph Ndieyira, Moyu Watari and coworkers used cantilever arrays – tiny levers no wider than a human hair – to examine the process which ordinarily takes place in the body when vancomycin binds itself to the surface of the bacteria. They coated the cantilever array with mucopeptides from bacterial cell walls and found that as the antibiotic attaches itself, it generates a surface stress on the bacteria which can be detected by a tiny bending of the levers. The team suggests that this stress contributes to the disruption of the cell walls and the breakdown of the bacteria.
The interdisciplinary team went on to compare how vancomycin interacts with both non-resistant and resistant strains of bacteria. The 'superbugs' are resistant to antibiotics because of a simple mutation which deletes a single hydrogen bond from the structure of their cell walls. This small change makes it approximately 1,000 times harder for the antibiotic to attach itself to the bug, leaving it much less able to disrupt the cells' structure, and therefore therapeutically ineffective.
"There has been an alarming growth in antibiotic-resistant hospital 'superbugs' such as MRSA and vancomycin-resistant Enterococci (VRE)," said Dr McKendry. "This is a major global health problem and is driving the development of new technologies to investigate antibiotics and how they work.
"The cell wall of these bugs is weakened by the antibiotic, ultimately killing the bacteria," she continued. "Our research on cantilever sensors suggests that the cell wall is disrupted by a combination of local antibiotic-mucopeptide binding and the spatial mechanical connectivity of these events. Investigating both these binding and mechanical influences on the cells' structure could lead to the development of more powerful and effective antibiotics in future."
"This work at the LCN demonstrates the effectiveness of silicon-based cantilevers for drug screening applications," added Professor Gabriel Aeppli, Director of the LCN. "According to the Health Protection Agency, during 2007 there were around 7,000 cases of MRSA and more than a thousand cases of VRE in England alone. In recent decades the introduction of new antibiotics has slowed to a trickle but without effective new drugs the number of these fatal infections will increase."
The research was funded by the EPSRC (Speculative Engineering Programme), the IRC in Nanotechnology (Cambridge, UCL and Bristol), the Royal Society and the BBSRC.
Notes for Editors:
For further information, to speak to Dr Rachel McKendry, or to obtain a copy of the paper ("Nanomechanical Detection of Antibiotic Mucopeptide Binding in a Model for Superbug Drug Resistance"), please contact Dave Weston in the UCL Press Office on +44 (0) 20 7679 7678 or email: email@example.com. For out of hours enquiries call +44 (0) 7917 271 364.
Images: This image is available by contacting the UCL Press Office (see above)
A schematic representation to show the nanomechanical detection of antibiotic-peptide interactions on multiple cantilever arrays. The blue and white structures show chemical binding interaction between vancomycin and the bacterial mucopeptide analogue, DAla. The red line represents the mechanical connectivity of the chemically reacted regions on the cantilever.
About the paper and authors:
The article 'Nanomechanical Detection of Antibiotic Mucopeptide Binding in a Model for Superbug Drug Resistance' was published in Nature Nanotechnology, October 12 2008
J. W. Ndieyira1,2#, M. Watari1#, A. Donoso-Barrera1, D. Zhou3,4, M. Vogtli1, M. Batchelor,3 M.A. Cooper5, T. Strunz1, M. A. Horton,1 C. A. Abell3, T. Rayment6, G. Aeppli1 & R.A. McKendry1.
# These authors contributed equally
1) London Centre for Nanotechnology and Departments of Medicine and Physics, University College London.
2) Jomo Kenyatta University of Agriculture and Technology, Department of Chemistry, Kenya.
3) Department of Chemistry, University of Cambridge.
4) School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds.
5) Institute for Molecular Bioscience, University of Queensland, Australia.
6) School of Chemistry, University of Birmingham.
About the London Centre for Nanotechnology:
The London Centre for Nanotechnology is an interdisciplinary joint enterprise between University College London and Imperial College London. In bringing together world-class infrastructure and leading nanotechnology research activities, the Centre aims to attain the critical mass to compete with the best facilities abroad. Research programmes are aligned to three key areas, namely Planet Care, Healthcare and Information Technology and bridge together biomedical, physical and engineering sciences. Website: www.london-nano.com
About UCL (University College London):
Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. In the government's most recent Research Assessment Exercise, 59 UCL departments achieved top ratings of 5* and 5, indicating research quality of international excellence. UCL is in the top ten world universities in the 2007 THES-QS World University Rankings, and the fourth-ranked UK university in the 2007 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. Website: www.ucl.ac.uk