Intense X-rays pave the way for better antibacterial drugs

Embargoed until 7.30pm GMT Thursday 2^nd 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

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).

²http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1226996060308?p=1204186170287

Silvana Damerell at Diamond: 0044 (0) 1235 778238/ 07841 432780 / silvana.damerell@diamond.ac.uk

Sarah Bucknall at Diamond: 0044 (0) 1235 778639 / 07920 296957 / sarah.bucknall@diamond.ac.uk

Isabelle Boscaro-Clarke at Diamond 0044 (0) 1235 778130 / 07990 797916 / isabelle.boscaro-clarke@diamond.ac.uk

For images, visit:ftp://ftpanon.diamond.ac.uk/WCSJ2009/Quinolone drugs - latest research

Notes to Editors

Diamond Light Source

• Diamond generates extremely intense pin-point beams of synchrotron light of exceptional quality ranging from x-rays, ultra-violet and infrared. For example Diamond’s x-rays are around 100 billion times brighter than a standard hospital X-ray machine or 10 billion times brighter than the sun.
• Many of our everyday commodities that we take for granted, from food manufacturing to cosmetics, from revolutionary drugs to surgical tools, from computers to mobile phones, have all been developed or improved using synchrotron light.
• Diamond will bring benefits to:
  • Biology and medicine. For example, the fight against illnesses such as Parkinson's, Alzheimer's, osteoporosis and many cancers will benefit from the new research techniques available at Diamond.
  • The physical and chemical sciences. For example, in the near future, engineers will be able to image their structure down to an atomic scale, helping them to understand the way impurities and defects behave and how they can be controlled.
  • The Environmental and Earth sciences. For example, Diamond will help researchers to identify organisms that target specific types of contaminant in the environment which can potentially lead to identifying cheap and effective ways for cleaning polluted land.