Antibiotic’s Fascinating Journey Through Time Unveiled in Recent Study

In modern medicine, antibiotics play a central role in the treatment of bacterial infections. In nature they are produced by bacteria or fungi, which they also use to defend themselves against other bacteria. Using a group of glycopeptide antibiotics, which, like teicoplanin and vancomycin, form a valuable reserve in medicine against highly resistant pathogens, a research team examined the evolution of this class of substances and reconstructed a hypothetical uranium antibiotic. Dr. Demi Iftime and Dr. Martina Adamek carried out the interdisciplinary project under the leadership of Professor Evi Stegmann and Professor Nadine Ziemert from the Cluster of Excellence “Control of Microorganisms to Combat Infections” at the University of Tübingen, supported by Professor Max Cryle and Dr. Mathias Hansen from Monash University in Australia.

Using bioinformatics methods, the researchers determined what the chemical composition of the precursor to today’s glycopeptide antibiotics might have looked like and how it was transformed by evolution. From this they gain insights into how current antibiotics could be further developed for medical use. Their study was published in the journal Nature Communications .

Determination of a family tree

“Antibiotics are originally primarily the products of a constant evolutionary conflict between different organisms, each of which tries to destroy its competitors or opponents or at least to prevent them from spreading,” explains Evi Stegmann. In its study, the research team used teicoplanin and vancomycin as well as a number of similarly structured antibiotics as starting materials. The natural products can each be isolated from specific bacterial strains. As the name glycopeptide antibiotics describes, chemically they consist of amino acids and sugars. They cause bacteria to die by preventing their cell wall development. In this way, teicoplanin and vancomycin also work against numerous human pathogens.

In biological relationship analyses, different species are usually placed in a tree structure in which the branches provide information about the degree of relationship. “In a very similar way, we placed the known glycopeptide antibiotics with their chemical structure, encoded by the gene clusters that contain their blueprints, into such a lineage tree,” says Ziemert. “Using computer algorithms from bioinformatics, a presumed original form of antibiotics can be calculated from the trunk of the tree, so to speak.” They named this hypothetical precursor Paleomycin. The research team assembled the identified genes that may have already encoded the biosynthesis of paleomycin and allowed a bacterium to produce the corresponding substance – paleomycin actually had an antibiotic effect in the test. “It was very exciting to create such an ancient molecule, like bringing a dinosaur or a woolly mammoth back to life,” reports the researcher.

Simplifying the structure

“What is interesting to us as a result is that, according to the calculations, all glycopeptide antibiotics come from a single precursor,” says Stegmann. “On the other hand, it was found that paleomycin has a similarly complex peptide structure in the core of the molecule as teicoplanin.” In contrast, this core structure is simplified in the case of vancomycin. “We assume that this simplification only emerged in recent evolution. However, the functionality as an antibiotic remained with the same mechanism,” says Ziemert. “These can be very useful for the bacteria that produce such antibiotics. However, these are substances with a complex chemical structure that cost the bacterium a lot of energy. Simplification with the same function could offer an evolutionary advantage.”

The researchers compared the family tree of the various glycopeptide antibiotics with a family tree of the bacterial strains that produce them. Starting with paleomycin, they carried out the changes in the chemical structure of the antibiotics – or those of the underlying gene clusters in the bacteria – meticulously and step by step. In doing so, they determined which key steps have to take place at approximately the same time in order to create a functional molecule. Scientists in Australia were able to reproduce some of these steps biochemically in the laboratory. “From this journey through time, we gained deep insights into the evolution of the metabolic pathways of antibiotic production in bacteria and nature’s optimization strategies that led to modern glycopeptide antibiotics,” says Ziemert. “This gives us a basis for further developing this important group of antibiotics using technical methods.”