Structure mediating spread of antibiotic resistance identified
9 January 2009
The research, funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), also sheds light on how antibiotic resistance genes spread from one bacterium to another. The research may help scientists develop novel treatments for these diseases and novel ways to curtail the spread of antibiotic resistance.
Antibiotic resistance spreads when genetic material is exchanged between two bacteria, one of which has mutated to be resistant to the drugs. This exchange is facilitated by a multi-component device known as a type IV secretion system, which acts to transport antibiotic resistance genes from within one cell, through its membrane and into a neighbouring cell.
Type IV secretion systems also play an essential role in transporting toxins or proteins from within bacteria into the cells of the body, causing diseases. Examples of Gram-negative bacterial pathogens using such a device are Helicobacter pylori (which causes peptic ulcers), Legionella pneumophila (which causes legionnaires' disease), and Bordetella pertussis (which causes whooping cough).
Now, in a paper published in the journal ‘Science’, scientists from the Institute of Structural and Molecular Biology (ISMB) at Birkbeck, University of London, and UCL (University College London) describe the structure of the core complex of a type IV secretion system, viewed using cryoelectron microscopy (a form of electron microscopy where the sample is studied at very low temperatures).
"Type IV secretion systems play key roles in secreting toxins which give certain bacteria their disease-causing properties and, importantly, are also directly involved in the spread of antibiotic resistance," says Professor Gabriel Waksman, Director of the ISMB and lead author of the study. "This is why they have become obvious targets in the vast effort required to fight infectious diseases caused by bacteria."
Gram-negative bacteria have a double membrane. At the core of the type IV secretion system is a double-walled chamber that spans the two membranes and opens at one side. Dr Waksman believes this chamber may offer a new pathway for targeting these bacteria.
"If we can inhibit the secretion systems that mediate transfer of antibiotic resistance genes from one bacterial pathogen to another, we could potentially prevent the spread of antibiotic resistance genes," he says. "For those pathogens that use type IV secretion system for secretion of toxins, the system can be targeted directly for inhibition. In both cases, this would have a considerable impact on public health."
Type IV secretion systems were first discovered in Agrobacterium tumefaciens, which uses the system to transfer tumour-inducing DNA into plants, causing "crown gall", which can be devastating to crops such as grape vines, sugar beet and rhubarb. However, crop scientists have been able to successfully exploit this transfer system as a way of introducing new genes into industrial crops, conferring herbicide-resistance and resistance to pathogens.
Image: 3D view of the structure of the type IV secretion system core complex; courtesy of R Fronzes and G Waksman.
Contact
Craig Brierley
Media Officer
Wellcome Trust
T +44 (0)20 7611 7329
E
c.brierley@wellcome.ac.uk
Notes for editors
1. Fronzes, R et al. Structure of a Type IV Secretion System Core Complex. Science. 9 January 2009 [Epub ahead of print]
2. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
3. The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £420 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
4. Birkbeck, University of London, was founded in 1823. It is a world-class research and teaching institution and a vibrant centre of academic excellence. Over 90 per cent of Birkbeck academics are research-active – the highest rate for any multi-faculty institution in London and the fifth highest in the UK. The 2008 Research Assessment Exercise placed Birkbeck research in the top 25 per cent of multi-faculty institutions in the UK. In 2006 Birkbeck was awarded a prestigious Queen’s Anniversary Prize for excellence in higher education research.