Cells optimized to produce antimicrobial agents

Big changes are taking place in the research laboratories at DTU Biosustain on Lyngby Campus—but it requires a microscope to spot them, as the changes are occurring in microorganisms such as the bacterium, Streptomyces.  The bacterium is known to produce antimicrobial agents. In the New Bioactive Compound Section, researchers are using ‘metabolic engineering’ to modify the bacterium to produce new bioactive substances. The substances may have different properties that are beneficial to humans—including anti-cancer and anti-aging properties—but the section has a particular focus on substances that can be developed into new antimicrobial agents. This focus is necessary, according to Section Head and Scientific Director Sang Yup Lee. In a recent video presentation of the section’s work, he stated:

“The pharmaceutical industry is no longer developing new antimicrobial agents because it is unprofitable. If they spend a lot of money developing new antimicrobial agents, the aim is to have them as ‘last resort’ which they keep for themselves until no other antimicrobial agents work.”

‘Click-to-go’

One of the research section projects has been to modify Streptomyces, so that the bacterium was able to absorb an artificial molecule produced by the researchers. Inside Streptomyces, the artificial molecule then forms part of the bacterium’s production of an antimicrobial agent. This antimicrobial agent will now have a new molecular composition. This could potentially mean the creation of a new antimicrobial agent to which no bacteria are resistant—but this has not yet been proven. ‘Click-to-go’ solutions are a rapidly growing area of global research, as it is a promising way to get microorganisms to produce many different substances. While the solution sounds simple, it is far from it, as the modifications have required a great deal of effort, assures Professor Tilmann Weber, DTU Biosustain:

“The solution is extremely difficult to perfect. The functions inside a bacterium that are responsible for the production of bioactive substances such as antimicrobial agents are exceedingly complex. It has required a lot of knowledge about biosynthesis inside the bacterium and subsequently a great deal of ‘engineering’ before we succeeded in getting the artificial molecule attached to the antimicrobial agent inside the Streptomyces bacterium.”

Drives large database

In order to exploit microorganisms in the development of new antimicrobial agents, researchers need to know the genes that enable organisms to produce the desired substances. The computer program and antiSMASH database developed by the New Bioactive Compounds research section together with colleagues in the Netherlands—and now run by the research section—is an important backbone in the development of new antimicrobial agents. Next year, the computer program will celebrate its 10th anniversary and in that time, it has become the world’s most widely used tool for researchers wanting to search between the genetic codes responsible for the production of bioactive substances by microorganisms.The database is freely accessible to all, says Professor Tilmann Weber: “It’s a service to society used by researchers from all over the world. The database and software are constantly being expanded with new data on the genomes of microorganisms—data coming from our colleagues around the globe.”

This summer, the total number of searches in the database over the ten years it has existed reached 700,000.