Saturday 15 June 2013

Antibiotic Resistance Using Crystallography


Scientists at the University of Bristol, together with collaborators at the University of Aveiro, Portugal, have solved the structure of an enzyme that breaks down carbapenems , antibiotics 'of last resort' which, until recently, were kept in reserve for serious infections that failed to respond to other treatments.

Carbapenemases are members of the group of enzymes called beta-lactamases that break down penicillins and related antibiotics.

Using molecular dynamics simulations, Professor Adrian Mulholland in the School of Chemistry and Dr Jim Spencer in the School of Cellular and Molecular Medicine, showed how a particular type of carbapenemase enzyme reorients bound antibiotic to promote its breakdown and render it ineffective.

In a study published in the Journal of the American Chemical Society (JACS), the scientists combined laboratory experiments with computer simulations to investigate how one particular type of carbapenemase recognises and breaks down antibiotics.

Using X-ray crystallography, they obtained two 'snapshots' of the carbapenemase in the act of breaking down a carbapenem antibiotic. This static structural information was used as a starting point for simulations that modelled the motions of the enzyme and the bound antibiotic.

The simulations showed how the carbapenemase reorients the drug to promote its breakdown. In beta-lactamases that cannot break down carbapenems, this rearrangement cannot happen, and so the enzyme cannot break down the antibiotic. Knowing this should help in designing new drugs that can resist being broken down.

For further details, see:

Fátima Fonseca, Ewa I. Chudyk, Marc W. van der Kamp, António Correia, Adrian J. Mulholland, James Spencer. The Basis for Carbapenem Hydrolysis by Class A β-Lactamases: A Combined Investigation using Crystallography and Simulations. Journal of the American Chemical Society, 2012; 134 (44)

Posted by Tim Sandle

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