Study looks to separate side effects from antibiotic activity

A new project is investigating whether altering the production of an antibiotic will remove side effects preventing it being used clinically to battle drug-resistant superbugs.

Tunicamycin is an antibiotic produced by the soil bacterium Streptomyces that was discovered 40 years ago. It works by blocking cell wall production in bacteria in a clinically novel way, making it potentially a very attractive candidate for treating antibiotic-resistant pathogens. However, it hasn’t been developed for use as a drug as it also affects crucial enzymes in our own bodies, making it toxic.

In 2010 Professor Mervyn Bibb of the John Innes Centre, in collaboration with the group of Professor Ben Davis at the University of Oxford, discovered the cluster of genes Streptomyces uses to make tunicamycin. Now, with £460,000 of funding from the Biotechnology and Biological Sciences Research Council, a new project will work out the steps Streptomyces uses to synthesise tunicamycin. The ultimate aim is rationally alter the synthesis in such a way that the antibiotic is still active against bacteria but lacks the serious side effects.

The structure of tunicamycin, (Nature Chemistry 4, 539–546 doi: 10.1038/nchem.1351)

Knowledge of the genes is vital to understanding the biosynthesis of tunicamycin, as it allows the enzymes and components to be produced and studied. Tunicamycin has a modular structure, so modifications can be designed and assessed in a systematic way to create analogues of the antibiotic. These analogues can then be tested for their ability to more selectively kill bacteria that cause diseases.

The researchers have taken the first step to understanding the molecular detail of how tunicamycin is synthesised by working out how two enzymes work together in the first committed step towards making the antibiotic. In collaboration with the University of Oxford, Chungbuk National University, Korea and the University of York, Prof. Bibb demonstrated how this happens in a previously unseen way. Published in the journal Nature Chemistry, this led to new insights into tunicamycin biosynthesis.

The research also suggests that tunicamycin functions as an antibiotic by mimicking molecular components involved in bacterial cell wall formation. It is also likely that a different type of ‘biomimicry’ is involved in inhibiting human enzymes, causing the toxic side effects of tunicamycin. By teasing apart in detail these two different activities, the new project will suggest ways in which tunicamycin biosynthesis can be tweaked to provide a new clinically-useful antibiotic.

 

Reference: ‘Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates,’ Wyszynski et al, Nature Chemistry 4, 539–546 doi: 10.1038/nchem.1351
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