17-Feb-2022 - Eidgenössische Technische Hochschule Zürich (ETH Zürich)

New drug candidates identified in bacteria

Bacteria show great promise as a source of active ingredients

Using computer-​based genome analysis, researchers at ETH Zurich have now discovered a new class of natural products that might one day serve as antibiotics.

Animals, plants, fungi and bacteria – each and every organism carries a whole armoury of chemical compounds that enable it to interact with its environment, attract partners or deter enemies. Bacteria, among the oldest forms of life on earth, contain a host of complex chemical structures, accumulated over millions of years of evolution.

Many of these metabolites have proved highly effective as active ingredients in human medicine. Indeed, around one-​third of the medicinal drugs approved today are derived from natural products. This includes most antibiotics.

Unlocking the chemical mysteries of bacteria is, however, not all that easy. The snag is that many types of bacteria are difficult, if not impossible, to cultivate in the laboratory. And, frequently, it is only in tandem with other organisms that they produce natural products that are of interest to medicine.

The application of bioinformatics and modern DNA sequencing methods can significantly expedite the hunt for new active ingredients. Using this approach, a research team led by Jörn Piel, Professor of Microbial Interactions at ETH Zurich, has now discovered a new synthetic pathway for peptide natural products that appears to be widespread in bacteria. Their findings were recently published in the Proceedings of the National Academy of Sciences (PNAScall_made).

Narrowing down the options

It was by combing through vast digital libraries of bacterial genomes that the researchers found what they were looking for. First, they hunted for blueprints of peptides – small protein molecules – and then for the blueprints of enzymes that can modify these peptides. These enzymatic modifications generate complex natural products in the bacteria; many of those products display special activity or added stability.

Since the peptide blueprints characteristic patterns, the researchers were able to use search algorithms to find them. The blueprints for these peptide natural products are stored in compact form in the genome. And right next to this peptide gene is where the genes for the enzymes sit.

“These enzymes function in very different ways, meaning that peptide natural products have huge potential to deliver new active ingredients,” explains Florian Hubrich, one of the lead authors of the study.

From blueprint to natural product

The genome analyses suggested that the enzymes were the key to discovering a whole new class of natural products. The researchers sorted similar candidates into groups, classified according to the blueprints of the different enzyme types. In the process, they realised that in one of the largest groups the function of the enzymes was still unknown.

For three of the potential natural products from this group, the researchers then conducted lab tests to verify the computer predictions. To this end, they inserted the relevant genes into laboratory bacteria and analysed which substances the microorganisms actually produced. This led to the discovery that members of this new natural product class  are ring-​shaped peptide molecules with a fatty acid appendage.

Certain lipopeptides – peptides connected to fatty acids – are known to be active ingredients. The antibiotic daptomycin, for example, has a very similar structure. However, the biotech process required to produce this drug is still very complex.

This is because the bacterium in which the antibiotic is produced also generates a number of natural product variants, each with fatty acids of different lengths. Only one of these variants is used as a drug, which must then be purified from the bacterial cells using a complicated process. It is here that Piel sees the biggest benefit of this new class of natural products.

New antibiotic candidates still to be tested

Daptomycin and other lipopeptides are assembled from amino acids in the organism of origin by a giant enzyme specifically responsible for this. These giant enzymes are not easily accessible for genetic engineering purposes. By contrast, the new class of peptide natural products are easier to produce – in a process based on genetically modified bacteria. Moreover, this method can also be used to generate new natural product variants.

In just a few steps, the researchers are able to modify the blueprints of these natural products in order to create “customised” active ingredients. For example, the sequence of amino acids in the peptide backbone can be modified by means of mutations in the corresponding gene. Furthermore, this macro-​level genome analysis has identified a host of new enzyme candidates that could be combined with a peptide gene on a modular basis.

The present study describes a total of three enzymes that attach fatty acids of differing chain lengths to a peptide. “Initial experiments show that it is indeed possible to produce these customised lipopeptides in the lab,” says Anna Vagstad, another of the study’s lead authors. The next step will be to investigate the biological activity of this new substance class.

“There’s often minimal financial incentive for pharmaceutical companies to develop new antibiotics,” Vagstad says, “but we researchers can at least take the first step, which is to search for new active ingredients.”

Facts, background information, dossiers

  • genome analysis
  • natural products
  • antibiotics
  • bacteria
  • drug candidates
  • bioinformatics
  • DNA sequencing
  • peptides
  • lipopeptides

More about ETH Zürich

  • News

    Hydrogel keeps vaccines alive

    Most vaccines require constant refrigeration during shipment to remain effective. An international research team led by ETH Zurich has now developed a special hydrogel that vastly improves the shelf life of vaccines, even without refrigeration. The development could save many lives and lowe ... more

    Breaking down plastic into its constituent parts

    A team of ETH researchers led by Athina Anastasaki have succeeded in breaking down plastic into its molecular building blocks and in recovering over 90 percent of them. A first step towards genuine plastic recycling. The chemical industry has a long tradition of producing polymers. This inv ... more

    Like bacteria firing spearguns

    Biologists from ETH Zurich have discovered speargun-​like molecular injection systems in two types of bacteria and have described their structure for the first time. The special nanomachines are used by the microbes for the interaction between cells and could one day be useful as tools in b ... more

  • q&more articles

    Analysis in picoliter volumes

    Reducing time, costs and human resources: many basic as well as applied analytical and diagnostic challenges can be performed on lab-on-a-chip systems. They enable sample quantities to be reduced, work steps to be automated and completed in parallel, and are ideal for combination with highl ... more

    Investment for the Future

    This is a very particular concern and at the same time the demand placed annually on Dr. Irmgard Werner, who, as a lecturer at the ETH Zurich, supports around 65 pharmacy students in the 5th semester practical training in “pharmaceutical analysis”. With joy and enthusiasm for her subject sh ... more

  • Authors

    Prof. Dr. Petra S. Dittrich

    Petra Dittrich is an Associate Professor in the Department of Biosystems Science and Engineering at ETH Zurich (Switzerland). She studied chemistry at Bielefeld University and the University of Salamanca (Spain). After completing her doctoral studies at the Max Planck Institute for Biophysi ... more

    Dr. Felix Kurth

    Felix Kurth studied bioengineering at the Technical University Dortmund (Germany) and at the Royal Institute of Technology in Stockholm (Sweden). During his PhD studies at ETH Zurich (Switzerland), which he completed in 2015, he developed lab-on-a-chip systems and methods for quantifying me ... more

    Lucas Armbrecht

    Lucas Armbrecht studied microsystems technology at the University of Freiburg (Breisgau, Germany). During his master’s, he focused on sensors & actuators and lab-on-a-chip systems. Since June 2015, he is PhD student in the Bioanalytics Group at ETH Zurich (Switzerland). In his doctoral stud ... more

q&more – the networking platform for quality excellence in lab and process

The q&more concept is to increase the visibility of recent research and innovative solutions, and support the exchange of knowledge. In the broad spectrum of subjects covered, the focus is on achieving maximum quality in highly innovative sectors. As a modern knowledge platform, q&more offers market participants one-of-a-kind networking opportunities. Cutting-edge research is presented by authors of international repute. Attractively presented in a high-quality context, and published in German and English, the original articles introduce new concepts and highlight unconventional solution strategies.

> more about q&more

q&more is supported by: