Date Published: 9 November 2012

Why can carbapenemases can destroy carbapenems while other beta-lactamases cannot ?

Scientists have recently revealed new information about the structure of carbapenemases, which are enzymes that break down antibiotics called carbapenems.

Carbapenems have been called the antibiotics 'of last resort' and have, until recently, been kept in reserve for serious infections that failed to respond to other treatments. However, bacteria such as E. coli are increasingly resisting the action of carbapenems by producing enzymes (carbapenemases) that break a specific chemical bond in the antibiotic, destroying its antimicrobial activity.

The enzymes carbapenemases are members of the group of enzymes called beta-lactamases that break down penicillins and related antibiotics, but it has not been clear why carbapenemases can destroy carbapenems while other beta-lactamases cannot.

Using molecular dynamics simulations, Prof Adrian Mulholland of the School of Chemistry at Bristol University (England) and Dr Jim Spencer of 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.

Professor Mulholland said:

" The class of antibiotics called carbapenems, drugs related to penicillin, are increasingly important in healthcare as treatments for bacterial infections. Until recently, carbapenems were 'antibiotics of last resort' but the growing problem of resistance to other drugs in organisms like E. coli (the leading cause of bloodstream infections in the UK) means that carbapenems are now becoming first-choice antibiotics for these infections. This is a worry because there are very few other treatment options for these organisms. Few new antibiotics effective against these pathogens are reaching the clinic.

_The recent appearance and spread of bacteria that resist carbapenems is a serious and growing problem: potentially, we could be left with no effective antibiotic treatments for these infections. The emergence of bacteria that resist carbapenems is therefore very worrying."

The scientists combined practical laboratory experiments with computer simulations to find out how one type of carbapenemase recognises and breaks down antibiotics. Using X-ray crystallography, they obtained two 'snapshots' of the carbapenemase in the process 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. This information may help scientists to develop new drugs that can resist being broken down.

Dr Spencer said:

" Combining laboratory and computational techniques in this way gave us a full picture of the origins of antibiotic resistance. Our crystallographic results provided structures which were the essential starting point for the simulations and the simulations were key to understanding the dynamic behaviour of the enzyme-bound drug.

_ Identifying the molecular interactions that make an enzyme able to break down the drug, as we have done here, is an important first step towards modifying the drug to overcome bacterial antibiotic resistance."

This research was conducted by scientists at Bristol University (England) in collaboration with colleagues at Aveiro University (Portugal).

Ref. to Paper
'The Basis for Carbapenem Hydrolysis by Class A β-Lactamases: A Combined Investigation using Crystallography and Simulations' by Fátima Fonseca , Ewa I Chudyk , Marc Willem van der Kamp , António Correia , Adrian J. Mulholland , and James Spencer in JACS (Journal of the American Chemical Society).

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