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Scientists have created the first detailed molecular blueprints of a bacterial enzyme called Lit, which is suspected of playing a “secret” role in the progression of the infection by reducing the immune response.
Blueprints like these allow drug developers to uncover potential weaknesses in bacterial arsenals as they try to develop new therapeutics that can help us win the battle against antibiotic resistance.
The study, led by scientists from the School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute (TBSI) at Trinity College Dublin, has just been published by a leading international journal Nature communication.
Lipoproteins and their role in bacterial infections
Lipoproteins fulfill a variety of functions in the bacterial cell. Some are essential for survival while others play an important role by interacting with the host’s innate immune response.
The growing list of enzymes responsible for building lipoproteins includes the recently discovered Lit (lipoprotein intramolecular transacylase), which produces a specific lipoprotein that “cools the immune response” – increasing the likelihood that Lit will allow bacteria to do so to secretly gain a foothold in the host
To understand how Lit works at the molecular level, the team led by Trinity just created the important, high-resolution crystal structure of Lit from Bacillus cereus – a common bacterium found in soil and food.
In combination with other analysis techniques, molecular dynamics simulations and quantum mechanical approaches, the team now has a detailed understanding of how it works.
Professor Martin Caffrey, Fellow Emeritus (Trinity and TBSI), is the lead author of the research. Underlining its importance and its potential social impact, he said:
“We believe that Lit is very likely a virulence factor that negatively affects the host’s immune response to infection. As such, it could prove to be a major target in the development of much-needed antibiotics that are less likely to develop resistance. And it’s no exaggeration to say that antibiotic resistance is a real, growing threat to our society.
“With a high-resolution crystal structure and a solid foundation for understanding how it works in bacterial cells, we are in a similar position to our position four years ago when we published similar work on a related lipoprotein processing enzyme known as lipoprotein signaling, Peptidase II (or LspA). LspA is currently under intense investigation as an antibiotic target by several research groups – including ours in TBSI – and a number of pharmaceutical companies. “
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This research was supported by funding from the Science Foundation Ireland, the Irish Research Council, the German Research Foundation, the European Union’s Horizon 2020 research and innovation program under the Marie Sk? Odowska-Curie grant agreement, and the Northern Irish Department of Agriculture, Environment and rural affairs.
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