Waking sleeping antibiotics
Soil bacteria can produce a wealth of antibiotics that are new to us, claims Gilles van Wezel. His group has developed a method that can rapidly identify and produce these unknown compounds. In Chemistry & Biology (Cell Press, online from 8 May) the researchers demonstrate that the approach works.
Doctors prescribe antibiotics for bacterial infections. The majority of these are produced by fungus-like soil bacteria of the Streptomyces genus. ‘But these are only the compounds that these bacteria secrete under standard laboratory conditions,’ says Gilles van Wezel, Professor of Molecular Biotechnology in Leiden. ‘They produce many more substances under stress, and it is very possible that previously unknown classes of antibiotics exist.’
New antibiotics would come in useful, because some pathogens have become insensitive to almost all used antibiotics. The big pharmaceutical firms no longer develop new antibiotics now the number of substances that can be produced under standard conditions, and therefore easily, is becoming exhausted. ‘This is why sleeping antibiotics from Streptomyces bacteria are so interesting,’ says Van Wezel. ‘We can wake them by adding activating molecules to the bacterial culture. But it was tricky to classify the promising compounds that then appear.’ Jacob Gubbens, also from Leiden University, has developed a method that makes this possible and fast. Gubbens and Van Wezel came up with the name ‘proteomining’ for this: mining in proteins.
How do they find out about an unknown compound? Van Wezel and Gubbens assume that a bacteria that produces such a complex compound initiates a whole production process in which all sorts of enzymes (proteins) make the different steps in this process possible. The good thing about bacteria is that the genes that code for such a set of enzymes are often close in the DNA. ‘Imagine we have a bacteria in mind that produces a promising antibiotic,’ explains Van Wezel. ‘We then culture it under different circumstances and determine when it produces a lot, a little or none. We then search for all proteins that appear together with the antibiotic. If we find proteins that are only active when the compound is made and whose genes are close in the DNA, we then have the DNA that contains the information on the antibiotic.’
This puts the researchers a step further. So much is known about DNA that they can recognise genes in it, know which type of enzymes they code for and what these enzymes do. They therefore gain an idea of the structure of the intended compound. Van Wezel: ‘This greatly accelerates the classification. We can also find clues to help increase the production of the compound. Unused antibiotics are therefore emerging, which could make it more attractive for the pharmaceutical industry to come on board.’ They have therefore patented the method. Other natural substances, such as medicines for cancer or fungal infections, could also be traced with this method.
(13 May 2014)
Health, Life and Biosciences is one of the six themes for research at Leiden Univesity.