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Sustainable Chemistry: Research team develops more environmentally friendly antibiotics

2017-11-15 Ciprofloxacin is a widely used broad-spectrum antibiotic. Like other antibiotics, after their use in medical applications, they wind up in the environment, where they remain unchanged and active. Even small concentrations of the active substance promote the growth of resistant bacteria. The team led by Professor Dr. Klaus Kümmerer has now succeeded in developing antibiotics of this class of substances that become innocuous in the environment by natural degradation.

Professor Dr. Klaus Kümmerer and Dr. Christoph Leder(r.) in the lab.

In Germany, human and veterinary medicine use around 33 metric tons of the active ingredient ciprofloxacin. A figure, which is still increasing. Like many other medicines, ciprofloxacin neither disaggregates, nor biodegrades in the environment after excretion from the body. Rather, the active ingredient accumulates in bodies of water, their sediments or in sewage sludge. If it is then used as fertiliser, ciprofloxacin ends up in soils. Antibiotics, when used in animal husbandry, are introduced directly into the soil by the spread of liquid manure. There, as in bodies of water and sediments, ciprofloxacin can favour the propagation of resistant bacteria. Food crops absorb ciprofloxacin in a similar way to other active pharmaceutical ingredients. Professor Dr. Klaus Kümmerer's researcher team resolves this massive and dangerous environmental pollutant by taking a "benign by design" approach, which builds new molecules in such a way as to make them more environmentally friendly. 

Researchers at Leuphana University of Lüneburg have been working for five years on the development of an antibiotic issued from ciprofloxacin, which decays and ceases to be active after its medical use. Leuphana University has filed for patent protection of the new active ingredients. "We have now developed active ingredients which produce good test-tube results, yet do not constitute a fully-fledged medicinal product", Kümmerer revealed. This was, he added, the task of potential partners in the pharmaceutical industry.

"We have had to become closely acquainted to the molecule"

Ciprofloxacin was selected because of its frequent use and its long-term environmental impact. "We have had to become closely acquainted to the molecule", Dr. Christoph Leder recounted. The crux of the matter: The active ingredient will not decompose unless its chemical bonds have been ingeniously debilitated so as to remain sufficiently stable in, for example, the blood stream, but then bio-degrade after having left the human body. The scientific assistant and biochemist Leder was instrumental in the development of the more environmentally friendly antibiotics. The researcher had already worked in drug development before starting his activity at Leuphana. He can now look back on a new success: "We had the ideas, the skills and the support", the researcher observed. 

However, the third-party funding which the team of researchers received for this highly motivated research project should not be taken for granted. "We had to submit the application several times. Not everyone shared our conviction; it was deemed too risky", Kümmerer explained. Yet, in the end the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt) stepped in with a grant of €460,000. In 2015 already, the researchers succeeded in improving the biodegradability of a beta-blocker. Christoph Leder sums up by saying: "We proved that it's possible". "This success can become a 'game changer' – new molecules open up new market chances, in particular when environmental compatibility is built in from the start, Professor Kümmerer adds.

Biodegradable antibiotics are in high demand

Biodegradable antibiotics are in high demand: Ciprofloxacin alone is responsible for serious environmental pollution. Leder explains that "If one wanted to dilute the amounts used down to a safe concentration, one would need the volume of seven times the Lake Constance". The effects of antibiotics in waste water are particularly problematic. The drugs attack wild-type bacteria, but the mutants do not react and can continue to divide. “The entire sewage treatment process becomes an incubator for resistant bacteria," said Leder referring to results from Sweden (Gullberg et al. 2011). These new findings show that even lower concentrations than previously assumed provide an advantage for mutant bacteria. Thus, the strategy of "living with a certain unavoidable background concentration" could backfire. The target should be as low concentrations as possible. In the past, it has been suggested that substances should be removed or inactivated by technically advanced sewage treatment procedures. This comparatively expensive method is, however, often incomplete and, in an increasing number of cases, it is becoming apparent that it generates transformation products, some of which are even more toxic than the source materials. In addition, many countries do not have any classic sewage treatment plants at all, let alone those with advanced treatment systems. 

A sustainable approach that also helps those countries, which also have to meet their increasing water needs by reusing (waste) water, for example for food production, is urgently needed at the global level. The working group's thinking comes into play by, instead, trying to modify the substances so as to increase their biodegradability or causing them to become rapidly inactive, even without the need for extended wastewater treatment. Klaus Kümmerer's hopes are high that the degradability of antibiotics and other active pharmaceutical ingredients in the environment will become an approval criterion, as feasibility has now been demonstrated.

Publication cited in the text:

Erik Gullberg, Sha Cao, Otto G. Berg, Carolina Ilbäck, Linus Sandegren, Diarmaid Hughes, Dan I. Andersson. PLOSpathogens, July 2011 | Volume 7 | Issue 7 | e1002158

Prof. Dr. Klaus Kümmerer
Universitätsallee 1, C13.311b
21335 Lüneburg
Fon +49.4131.677-2893
Fax +49.4131.677-2848

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