Embargoed until 7.30pm GMT Thursday 2nd July 2009
London: A special family of antimicrobials called quinolones is currently used to treat virulent bacteria responsible for some of the most dangerous diseases such as pneumonia and meningitis. However, these bacteria tend to develop drug resistance, due to their rapid growth and mutation. Recent work throws important light on how quinolones operate on the bacterial DNA at the molecular level, and also how the DNA may evolve, allowing the bacteria to ‘fight back’. The results from research teams using Diamond, the UK’s national synchrotron, and SOLEIL, the French national synchrotron, could lead to a new approach to drug development by scientists in pharmaceutical companies.
Speaking today at the French Embassy, Dr Mark Sanderson, from King’s College London, presented the new results from his group, who have been working in collaboration with Prof Mark Fisher and his colleagues in the Molecular Genetics Group at St. George’s in London. The research, which was published in Nature Structural and Molecular Biology¹, uncovers the mechanism by which quinolone drugs interact with DNA and bacterial topoisomerase.
Stunning science - an electron density map of the quinolone binding sites of a topoisomerase IV - DNA complex. First published in Nature Structural & Molecular Biology
“New antibacterial drugs are desperately needed to combat infections caused by resistant bacteria, such as MRSA, for which conventional antibiotics are ineffective. Using the intense X-rays produced by the synchrotrons Diamond and SOLEIL, we now understand how quinolones interact at a molecular level with their bacterial targets. This knowledge will feed into the R&D programmes of drug companies who are developing the next generation of antibacterial drugs. “Facilities such as Diamond and SOLEIL are critical because they allow us to acquire the high resolution data required to answer important biological questions which our in-house X-ray sources could not obtain. A long term goal for research groups such as mine is to help understand how topoisomerases work at a molecular level in order to develop new drugs to overcome drug resistance”.
Dr Mark Sanderson, King’s College London
Back in the early 60s, a new family of antimicrobials know as quinolones was introduced, initially to treat urinary tract infections. These first generation topoisomerase inhibitors had limited activity and resistant strains soon developed. Second and further generation quinolones were developed that were more potent and had an improved spectrum of activity. Today, quinolones are the second line of defence against Streptococcus pneumoniae disease, which includes pneumonia, meningitis and peritonitis. In the USA, in the year 2000, Streptococcus pneumoniae infections were responsible for up to 135,000 hospitalisations for pneumonia, 6 million cases of otitis media and 60,000 cases of invasive disease, including 3,300 cases of meningitis. (Source: Centres for Disease Control and Prevention, USA).
Bacteria are becoming resistant to antibiotics for a number of reasons including a substantial increase in antibiotic usage, environmental and socioeconomic factors and increased international travel. As well as drug development, public awareness of the problem of antibiotic resistance is vitally important. Last year, the Heaith Protection Agency and its European partners developed and launched the first European Antibiotic Awareness Day (18th November 2008), an education project that is highlighting the dangers of inappropriate prescribing. The “e-Bug” scheme² will teach school children about prudent antibiotic use and the importance of good hygiene. By targeting the future generation of antibiotic users and making them aware of the dangers of inappropriate prescribing, the project aims to help control antibiotic resistance across Europe. Prudent use of current antibiotics and intelligent design of new drugs will both be needed to combat resistance.
¹ Nature Structural & Molecular Biology Volume 16 Number 6 June 2009 doi:10.1030/nsmb.1604. Funding for this research was provided by the Biotechnology and Biological Sciences Research Council (BBSRC), St George’s-University of London, the Guy’s and St Thomas’ Charitable Trust, and the UK Medical Research Council (MRC).
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For images, visit:ftp://ftpanon.diamond.ac.uk/WCSJ2009/Quinolone drugs - latest research
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