Antibiotic production controls unravelled to help in clinical development

Scientists researching a new antibiotic have pieced together the way it is produced by a soil bacterium by working out the functions of its genes.

Microbisporicin is produced by a soil bacterium from Indonesia called Microbispora corallina.

A clearer understanding of how microbisporicin’s synthesis is regulated by the bacterium will provide the basis for finding ways of optimising its production and so become a new weapon in the fight against multi-drug resistant pathogens.

Lantibiotics are a class of antibiotics produced by bacteria, and microbisporicin represents a potent example of the class, which has so far been under-exploited for clinical use. That could now change, as preclinical trials are showing that it is highly active against a large range of bacteria.

To aid its pharmaceutical development, Professor Mervyn Bibb and Dr Lucy Foulston at the John Innes Centre, which is strategically funded by the BBSRC, identified the genes that Microbispora corallina uses to regulate microbisporicin  production.

In new research published on the front cover of the Journal of Bacteriology, they have now produced a model of the regulatory mechanisms used to trigger its production, maintain it at a high level and also provide auto-immunity to the antibiotic’s effects.

“Prior to antibiotic production, the system is poised for activation,” said Professor Bibb. “We think that in response to some trigger, such as nutrient deficiency, a master regulator gene initiates microbisporicin synthesis.”

“The system has an auto-inducing mechanism, where intermediates or microbisporicin itself promote high level expression of the entire gene cluster, including essential immunity genes that ensure that the bacterium itself is not harmed by the antibiotic. It also has a safety mechanism – If immunity is knocked out, the strain doesn’t make the antibiotic and kill itself.”

As well as providing fundamental knowledge of the mechanisms controlling lantibiotic synthesis, this work also identifies genetic targets for manipulation.

Knowing precisely how the genes that encode the biosynthetic pathway interact and control the auto-induction and self-immunity mechanisms allows for a rational approach to increasing the level of microbisporicin during its development as a viable pharmaceutical.

Lucy Foulston was recently awarded a prize for Excellence in Scientific Research by the John Innes Foundation for her work on microbisporicin

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