Molecular blueprint of key bacterial enzyme may aid drug design

Posted on: 23 March 2018

Scientists, using next-gen crystallography techniques, have successfully blueprinted the molecular structure of a key bacterial enzyme known as BacA. The structure provides clues about how the enzyme works at a molecular level, which should offer insights into how it might be exploited for the design and discovery of new drugs.

An additional important milestone linked to the work is that the BacA blueprint is the first one produced using a novel experimental phasing method. The scientists behind the research developed the in situ method with colleagues at the Swiss Light Source, which allows them to gather the data they require without ever touching the (easily damaged) crystals that hold the all-important structural information.

The work was led by Professor Martin Caffrey, Fellow Emeritus in Trinity College Dublin’s School of Biochemistry and Immunology. It was recently published in leading international journal, Nature Communications (see here).

The blueprint of BacA also raised an interesting idea that the research team is now pursuing: the enzyme may be ‘double-jobbing’. They believe it may act not only as an enzyme (speeding up chemical reactions), but also as a ‘flippase’, where the chemical product it transports is the product of the reaction it speeds up.

Professor Caffrey said: “BacA is a complicated nanomachine with many working parts. The blueprint suggests that the powerstroke of the enzyme’s proposed flipping action is driven by the energy released in the exergonic reaction it catalyses.”

If their idea holds up, it would shed light on a flippase activity, which has long been sought-after in the field, as it is a key player in a cycle vital to bacterial function. At the same time, they are hot in pursuit of compounds that inactivate BacA, as these will serve as much-needed therapeutics to counter the global healthcare threat posed by antibiotic resistance.

To read more about this amazing work, and the story behind it, read Professor Caffrey’s post on the microbiology section of the natureresearch blog.