In order to artificially produce the naturally occurring substance, the scientists used what is known as relay synthesis - instead of immediately creating the entire complex molecule, they first synthesized the critical sections, which served as staging posts en route to the complete substance. The research success does not lie solely in the components produced, but in the proof of the development process.
The results have just been published in the renowned specialist scientific journal, Chemistry - A European Journal from Wiley-VCH, one of the leading scientific publishers in chemistry and materials science.
Neosorangicin A
Neosorangicin A is what is known as a secondary metabolite that is produced by myxobacteria in order to compete with other microorganisms. Existing research has shown that Neosorangicin A interferes in a central process in the bacteria in that it inhibits the bacterial RNA polymerase, that is, the enzyme that bacteria need in order to read their genetic information and multiply. So far, the substance has been effective against various groups of bacteria, including gram negative pathogens. These bacteria are increasingly causing problems for hospitals worldwide and are particularly difficult to treat, because they possess an additional protective outer layer that repels many active ingredients. Neosorangicin A is thus one of a class of substances that are of particular interest for the development of future reserve antibiotics.
“We are working here with a molecule that is extremely exciting biologically, but which in chemical terms poses great difficulties to study,” says Professor Dieter Schinzer. “The method of synthesis that has now been developed is the prerequisite for making targeted changes to the natural substance and making it more stable and thus usable for further active ingredient development.”
The Synthesis
Schinzer goes on to say that the challenging part of the synthesis was that Neosorangicin A is not only a really large molecule, but also that its three-dimensional structure is highly complex. “The molecule contains 16 so-called chiral centers, or in other, simpler, words places where the spatial arrangement of the atoms has to be extremely precise. Even the tiniest deviations can be critical when it comes to a substance fitting in the molecular “pocket” of its target protein or remaining ineffective.” Added to this, Neosorangicin A is relatively unstable and can be quickly degraded in the body. “And this is precisely why a chemical approach is so important. Only now that we have succeeded in replicating the molecule in the laboratory can it be chemically altered in targeted fashion and biologically optimized.”
Professor Schinzer and his team developed a convergent synthesis strategy. Instead of building the complex molecule in a long sequence step by step, the researchers initially produced three highly complex key building blocks separately and only combined them with one another at the end of the process. The production of individual sub-structures required up to 19 chemical reaction steps. With special coupling reactions they ultimately succeeded in building the complete carbon skeleton of Neosorangicin A.
Worldwide antibiotic resistance
The World Health Organization (WHO) considers antibiotic resistance to be among the greatest threats to global health. A global analysis published in 2024 in The Lancet estimated tresistance,1 around 1.14 million deaths were directly caused by bacterial resistance, and 4.71 million deaths were associated with it. By 2050, every year up to 1.91 million people could die directly as a result of resistant bacterial infections, if no more effective countermeasures are developed.
“Resistant infections are no longer an abstract future scenario, but instead have long been a global medical problem,” says Professor Schinzer. “We need new types of structure because many of the traditional antibiotics are losing their effectiveness. Natural substances such as Neosorangicin A can provide important models for this, but only if we learn how to control them chemically.”
Professor Schinzer adds that there is still a long way to go before an effective drug can be produced. The successful synthesis of Neosorangicin A does, however, provide a crucial foundation for this by making what has until now been a difficult to access natural substance chemically available and alterable. “This means that in future, more stable variants can be developed, biological effects tested and possible new drug candidates systematically investigated.
The research project, which was entitled “SME Innovative-21: NEOSORA” was supported by, among others, the Federal Ministry of Research, Technology and Space (BMFTR) within the SME Innovative program as well as the European Fund for Regional Development (EFRD) (ZS/2024/01/183363).
The Helmholtz Center for Infection Research supplied the natural reference sample of Neosorangicin A.
Chemistry - A European Journal
Experimental study
Lab-produced tissue samples
Relay Approach: A Convergent Synthesis of Key Fragments En Route to (+)-Neosorangicin A
2-Jul-2026