Press release | 27 January 2023 | wrt

Natural Plant Toxin As a New Broad-Spectrum Antibiotic

Researchers have modified albicidin - the trigger of leaf blight in sugar cane - making it effective against multi-resistant hospital germs

Working together with researchers from the United Kingdom and Poland, Professor Dr. Roderich Süssmuth’s Organic and Biological Chemistry Group at TU Berlin has used electron microscopy at low temperatures to create snapshots of how albicidin inhibits a vital enzyme in bacteria. By gaining a detailed understanding of this mechanism of action, they were then able to use computer simulations and chemical synthesis in labs to create variants of the original albicidin molecule that are effective against some of the most dangerous bacterial infections in hospitals. Their findings have now been published in the journal “Nature Catalysis.”

Multi-drug resistant pathogens such as Escherichia coli, Pseudomonas aeruginosa and Salmonella typhimurium represent a dangerous burden for healthcare systems, further exacerbated by the COVID-19 pandemic. Infections with resistant pathogens are one of the most common causes of death in intensive care units, with some strains becoming pan-resistant, meaning that all common antibiotics no longer work. More than 35,000 people die each year in Europe as a result of antibiotic resistances according to the European Centre for Disease Prevention and Control (ECDC). As a result, there is now an urgent search for new antibiotics which are effective against many bacteria and against which resistances cannot be so quickly developed.

Plant toxin albicidin offers new hope

A new source of hope is provided by the natural plant poison albicidin. As early as 2015, Roderich Süssmuth’s research group in cooperation with scientists from France was able to determine its chemical structure. Albicidin is produced by the bacterium Xanthomonas albilineans, which causes devastating leaf blight disease of sugar cane. The pathogen uses albicidin to attack the plant, transforming it into a host organism before spreading further.

In recent years, researchers have worked out how this bacterial strategy works. It targets an enzyme called DNA gyrase (or simply “gyrase”). This enzyme attaches to the DNA and underwinds it. This becomes important whenever the cell wants to divide and the DNA has to be copied completely to achieve this. However, gyrase has an Achilles’ heel: In order to fulfill its task, it has to cut the DNA double helix completely for a short time. This is a dangerous moment for the cell, because there is a risk that the DNA ends will not rejoin correctly. Normally, gyrase quickly rejoins the two pieces of DNA, but albicidin prevents this happening, resulting in damaged DNA and the death of the cell.

Also deadly for bacteria

However, albicidin has other uses too. The gyrase enzyme which it attacks to help destroy sugar cane is not found exclusively in plant cells; it is also present in bacteria.

In humans, too, there are related enzymes, but the differences to gyrase are sufficiently great that albicidin is highly unlikely to harm us. Importantly, the way albicidin interacts with gyrase is also sufficiently different from existing antibiotics, meaning that, after some chemical tweaking, albicidin is likely to be effective against most of current antibiotic-resistant bacteria, the so-called “superbugs.” This makes the substance one of the most important candidates for the eagerly awaited new broad-spectrum antibiotic.

Gaining an understanding of the mechanism of action using cryoelectron microscopy

“Despite its known potential as an antibiotic and its low toxicity in pre-clinical experiments, we still need to optimize the structure and composition of the albicidin molecule, which is rather large, before using it in medicine,” explains Roderich Süssmuth. “In chemistry, we speak of a 'rational design' of the molecule. However, this has so far been hampered by the fact that we did not know exactly how albicidin interacts with the gyrase.”

This led Professor Süssmuth’s research group to join forces with the lab teams of Dr. Dmitry Ghilarov at the John Innes Centre in Norwich (United Kingdom) and Professor Jonathan Heddle at Jagiellonian University in Kraków (Poland). Using a technique known as cryoelectron microscopy, they were able to effectively observe albicidin at work. Electron beams are used at low temperatures of below minus 150 degrees Celsius to capture processes at molecular level in thousands of snapshots without blurring. These revealed that albicidin forms a kind of L-shape and can thus interact in a unique way with both gyrase and DNA. In this state, the gyrase can no longer move to bring the DNA ends together. The effect of albicidin here is similar to a spanner thrown between two running gears to block them.

Bacteria will not form resistances so quickly

“It seems that because of the nature of the interaction, albicidin targets a really essential part of the enzyme, making it difficult for bacteria to develop resistance to it,” says Professor Süssmuth. Doctoral researcher Kay Hommernick adds: “Now that we have a structural understanding, we can increase the number of binding sites between albicidin and the gyrase and introduce further modifications to the molecule to improve its efficacy as well as its pharmacological properties.” Indeed, using computer visualizations, the team has already chemically synthesized variations of the antibiotic with improved properties. In tests, these variants proved effective against some of the most dangerous bacterial infections found in hospitals, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella typhimurium. Albicidin has proven highly effective even in small concentrations.

Sponsors sought for clinical trials

The next step for this research is to collaborate with other academic and industrial partners as well as seek funding to advance the research into human clinical trials, Süssmuth explains.

“If these prove successful, albicidin would create a whole new class of antibiotics - and could save the lives of many thousands of people every year.”


Organization name Organic and Biological Chemistry