US researchers have for the first time synthesised an important class of drug compounds - the aromatic polyketides - in Escherichia coli, a bacteria widely used in microbial production.
The aromatic polyketide class is one of the last remaining major classes of natural products of which the biosynthesis has not been achieved in E. coli, considered one of the best organisms for making compounds via microbial fermentation. Polyketides include the antibiotic tetracycline and the anticancer drug doxorubicin.
Researchers from the UCLA Henry Samueli School of Engineering and Applied Science led by principal investigator Yi Tang, dissected a polyketide synthase enzyme from a rice plant fungus, then reassembled it and transferred it into the bacterium. The synthetic enzyme was able to synthesise the carbon backbone of aromatic polyketides, something which was previously impossible in E. coli.
Once that step was achieved the researchers spliced in a series of other enzymes to create a new metabolic pathway in the bacterium that produced a range of bacterial aromatic polyketides from simple nutrients such as glucose.
Producing the drugs in E. coli has real advantages, say the authors, as it grows quickly, is relatively easy to engineer and has well-documented metabolic pathways that make it an ideal organism for mass production.
Many natural products used in pharmaceuticals are synthesised by organisms that are difficult to collect, grow and maintain, they add. E. coli is already used to make antibiotics like erythromycin and vancomycin, as well as terpenes and alkaloids, but attempts to synthesise bacterial aromatic polyketides have been hindered by the compounds' complicated assembly process.
"There are some beliefs that bacterial and fungal enzymes will not cross-talk to each other," said Wenjun Zhang, the paper's lead author.
"Our work showed that polyketide synthase from the two kingdoms can indeed be functionally combined inside the E. coli platform.”
The research was published in the December 30 edition of Proceedings of the National Academy of Sciences.