Stereomicroscopic image of Cystobacter violaceus in red.
Soil-living myxobacteria of the species Cystobacter violaceus, recorded here through a stereomicroscope, form substances known as cystobactamids, which kill other bacteria.

Antibiotics of the future?

Among all the hospital germs, Gram-negative bacteria are particularly difficult to treat: Many antibiotics fail due to the double-cell membrane. But cystobactamides are providing hope for a remedy – substances from the extensive collection of bacteria held by the HZI. These bacteria are going to be further developed into drugs in a partnership with the pharmaceutical company Evotec.

The collection of myxobacteria at the Helmholtz Centre for Infection Research (HZI) has proven time and again to be a real treasure trove. The soil bacteria, which were initially regarded as not cultivable, have been grown and researched on a large scale since the 1970s by the centre’s predecessor. The main collection has been continuously expanded since then. At the HZI and its Saarbrücken branch, the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), myxobacterial extracts have been examined for interesting natural substances – and the researchers are constantly being surprised.

“In 2011, for the first time, we identified a molecule that’s effective against Gram-negative bacteria, which we found in an extract from Cystobacter, a species of myxobacteria,” remembers Rolf Müller, myxobacteria researcher and Managing Director of the HIPS. Looking at other myxobacterial species, Müller and his colleagues later found other variants of the substance, which has since been given the name “cystobactamide”. It turned out that they had discovered a whole class of previously unknown molecules – and some of these work much more effectively and against a wider range of germs than the first variant they found. It is assumed that myxobacteria with substances such as cystobactamides are able to keep any unwanted competition for food from other bacteria at bay.

3D model of the structure of a cystobactamide molecule
3D model of the structure of a cystobactamide molecule.

The mode of action is promising: The cystobactamides are so-called gyrase blockers. They prevent the bacterium from unwinding the DNA in the way that is required for reproduction. “Gyrase blockers already exist and have been successfully used as antibiotics in clinical settings,” says Müller, “but many bacteria have become resistant to them.” Cystobactamides, on the other hand, continue to be effective against such germs. Together with the teams lead by Mark Brönstrup (HZI), Marc Stadler (HZI), Rolf Hartmann and Anna Hirsch (both from HIPS) and Andreas Kirschning (Leibniz Universität Hannover), Müller and his colleagues further improved the properties of cystobactamides, tested them in mice and developed methods for producing them in larger quantities in the laboratory.

In order to be able to turn these promising substances into drugs for hospitals, the HZI has secured a high-profile partner for the next stages: the pharmaceutical company Evotec, based in Hamburg.

“There’s still a lot to be improved in terms of the chemistry, the efficiency of the synthesis must be increased and the pharmaceutical properties need to be optimised. This would take us years on our own.”

Rolf Müller
myxobacteria researcher and Managing Director of the HIPS

And how quickly will things progress with Evotec as an industry partner, with whom the HZI has concluded a cooperation agreement for an initial period of three years? Müller is optimistic: “The risks in drug development are always high. But I hope that it’ll be possible to carry out clinical trials in humans within three to four years – and ideally, obtain market approval two to four years after that.”

Author: Manfred Braun

Published: May 2019