Unravelling Of NDM-1 Structure Signals Breakthrough In Fight Against Vicious Superbug

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Academic Journal
Main Category: MRSA / Drug Resistance
Also Included In: Infectious Diseases / Bacteria / Viruses
Article Date: 07 Sep 2011 - 2:00 PDT


News of a significant breakthrough in the fight against drug-resistant infections arrived this week in the form of a paper in the online journal Acta Crystallographica Section F: Structural Biology and Crystallization Communications where researchers describe how they unravelled the structure of NDM-1, a vicious type of superbug that is currently resistant to our most powerful antibiotics.

Drug resistance in infectious bacteria is on the rise, posing a serious threat to human health. More recently there have been raised concerns that antibiotics may soon be useless as the superbugs have begun to outsmart even the newest ones. Every year over 25,000 people die in Europe because of antibiotic resistant infections. The race to find new ways to fight them has never been so challenging.

An important part of the fight against superbugs is identifying key parts of their structure to help us find out how they "hydrolyse" and render ineffective the antibiotics designed to kill them. Much of their resistance comes from a group of enzymes known as the metallo-[beta]-lactamases (MBLs), the most recent new member being the recently identified New Delhi MBL 1 (NDM-1).

NDM-1 is particularly frightening because it makes bacteria resistant to our most powerful antibiotics, the carbapenems, which are our last line of defence against superbug infection. It has been found in a variety of bacteria, including the familiar E. coli.

The New Delhi or modified NDM-1 bacteria are thought to have entered the UK in patients returning from India and Pakistan who went there to take advantage of cheaper surgical procedures, such as cosmetic surgery. There was a lot of news about this in the second part of 2010.

So far only 70 cases of infection have been reported in the UK, but this small number does not lessen the urgency of the need to find a way to defeat this powerful superbug and save lives.

Now Medical Research Council (MRC) scientists at the Research Complex at Harwell (RCaH) in Oxfordshire, UK, have created a structural model of NDM-1 that will be a great help to researchers and pharma companies trying to develop new ways to overcome bacterial resistance and develop new treatments.

Professor Simon Phillips, who led the study and is director at the Research Complex at Harwell, told the press "NDM-1 is a serious threat to human health," and "is able to degrade many forms of antibiotic and render them useless".

"In addition, the gene for NDM-1 can be passed between different bacteria so can spread rapidly in the population and generate drug resistance in different diseases," he added.

Phillips said knowing the structure of the enzyme is the first step in understanding how the superbug works and leads the way to the design of drugs that might prevent its action. This study, which is supported by the MRC, is giving vital information to help speed up the development of new drugs, he added.

In their paper, the researchers report how they modelled the crystal structure of NDM-1 from Klebsiella pneumoniae, and discuss its "structure and active site ... in the context of other recently deposited coordinates of NDM-1".

Professor Sharon Peacock, a member of the Medical Research Council Infections and Immunity Board, said identifying the structure of NDM-1 is a "crucial step towards ensuring that drug development is based on a sound understanding of the mechanisms of bacterial resistance to antibiotics".

As well as Phillips's team, other centres nearby played a key role. For example, the Oxford Protein Production Facility-UK, which is also funded by the MRC and is based in the RCaH, rapidly prepared samples of the enzyme using just its genetic sequence. And the crystallography lab at the nearby Diamond Light Source, the largest UK-funded scientific facility to be built for over 40 years, determined the structure of the enzyme.

Written by Catharine Paddock PhD
Copyright: Medical News Today
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