Natural antibiotic genetically engineered from fungus

Japanese researchers have used a combination of genetic engineering and patience to turn a fungus into a natural antibiotic — one which could serve as a promising cure for a neglected tropical disease called human African trypanosomiasis.

Also known as African sleeping sickness, the disease is caused by a parasite that moves from flies, to humans’ bloodstreams, and then into the nerves of their brains and spinal cords. The disease infects thousands of people in remote, rural areas of sub-Saharan Africa each year, and is often fatal within three years.

Professor Kiyoshi Kita, who retired from the University of Tokyo in 2016, dedicated a large portion of his career to understanding and curing African sleeping sickness. A team led by Professor Ikuro Abe, from the university’s Department of Pharmaceutical Sciences, joined the project due to their expertise in mapping the chemical paths that lead from genes to proteins inside cells.

The fungus Acremonium egyptiacum naturally produces two different types of antibiotic. One is toxic to humans, but the other — ascofuranone — was identified as a potential treatment for African sleeping sickness in 1996 in part by Prof Kita. However, artificially synthesising the antibiotic would not be cost-effective and the more common method of using bacteria to produce the chemical was infeasible.

Prof Abe’s research team identified that the fungus’s two antibiotics are both made from the same precursor molecule — after the precursor is created, two separate groups of enzymes produce the two different antibiotics. So the team used their biosynthesis pathway expertise to genetically modify the fungus so that it produces large quantities of the desired antibiotic.

In every litre of fungus that scientists grow in the lab, the engineered strain of the fungus can produce 500 mg of antibiotic. The researchers can leave the precursor molecule and the genes responsible for the desired antibiotic completely unchanged by simply deleting the genes responsible for the other toxic antibiotic.

“The gene cluster in the fungus is unique — through a simple genetic deletion, we have engineered a strain of the fungus that only produces high concentrations of the desired antibiotic,” Prof Abe explained.

With their work now published in the Proceedings of the National Academy of Sciences, the researchers have applied for a patent on the engineered strain of fungus. Collaborators at the Kikkoman Corporation, best known for making soy sauce, will pursue industrial-scale growth of the genetically engineered fungus and purification of the antibiotic, which is also a candidate for cancer treatment.

Image caption: Acremonium egyptiacum growing in a dish. Image by Motomichi Matsuzaki, CC-BY

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