An international team of scientists have shown that they can modify a well-known antibiotic into new derivatives. The technique paves the way for new antibiotics, which can easily be assembled inside microbes using so-called “click chemistry”.
“Click!” – and your antibiotic is good to go. A new method allows scientists to click-on new side chains to an antibiotic backbone, opening new possibilities for designing improved antibiotics.
Being able to change existing antibiotics has big implications – amongst other to avoid antibiotic resistance – according to Senior Scientist Tilmann Weber from The Novo Nordisk Foundation Center for Biosustainability (DTU Biosustain):
“With this method, we can introduce modifications that can improve the pharmacological properties of the compound. In some cases, the modifications can even mean that the disease-causing microbes can no longer inactivate the antibiotic by cleaving it. Having such new molecular tools to rationally generate derivatives of complicated molecules therefore is very important for the development of new antibiotics”, he says.
Making antibiotics without harsh chemistry
Many current antibiotics are produced by bacteria such as Streptomyces. But often the antibiotic molecules produced by the microorganisms needs chemical modification in order to get the optimal pharmaceutical properties, for instance the right solubility or degradability.
Modifying an antibiotic chemically may require high temperatures, high pressure or harsh chemistry – or the wanted alterations may not even be possible to achieve.
"With this method, we can introduce modifications that can improve the pharmacological properties of the compound"
Senior Scientist Tilmann Weber, DTU Biosustain
But this is changing. With this new method to introduce handles for ‘click chemistry’, the scientists from DTU Biosustain have made it possible to tailor antibiotics inside the producing microbe.
“This is a very important technique, because it would actually be nearly impossible to make this modification chemically. Also, we can do this under very mild conditions within the cell, and thus avoid using harsh chemical reactions, as is often the case when you have to do modifications today,” Tilmann Weber says.
Developed easy click-on system
The scientists showed that this system works for the antibiotic kirromycin, which is a very complicated molecule synthesized by a large so-called polyketide assembly line.
At one defined position in the complex structure of kirromycin, the group managed to introduce an artificial unit with a triple bond structure that can specifically react with other molecules under very mild conditions. This triple bond works as a hook to which the desirable side chains can easily be clicked on to.
The next step is to transfer the system to other antibiotic pathways in order to insure the availability of efficient antibiotics. The research has been published in the journal ACS Synthetic Biology.