The infectious agents Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa are Gram-negative bacteria and much-feared around hospitals. Due to their double cell wall, these germs are difficult to control and are among the most harmful pathogens on the WHO's priority list. Scientists from the Helmholtz Centre for Infection Research (HZI), specifically from its branch facility, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), discovered the new substance class called cystobactamids. The natural products are capable of penetrating through the double cell membrane of Gram-negative bacteria and to kill these bacteria. The optimization of the lead structures for a use as broadband antibiotics will be continued in the scope of a new cooperation with Evotec AG.
"It is indispensable to build strategic partnerships with clinical experts and industry to assure the clinical translation of innovative drugs against harmful Gram-negative hospital germs, such as the cystobactamids, The alliance with Evotec as a long-term partner is therefore a major success and perfectly complements the expertise available at the HZI," says Prof Mark Brönstrup, who is the head of the department Chemical Biology at the HZI. "But the optimisation of the cystobactamids into a lead structure would not have been possible without the efficient cooperation of various research groups at the HZI and at the HIPS in Saarbrücken, at the Leibniz University in Hannover and at the DZIF."
The research team of Prof Rolf Müller at the HZI and at the HIPS successfully isolated a group of substances from the myxobacterium Cystobacter sp. that are effective against Gram-negative bacteria and others. The class is based on a novel chemical structure and has been named cystobactamids. The researchers in Saarbrücken also elucidated the mechanism of action. "We were able to show that these drugs act as so-called gyrase inhibitors. They prevent the DNA, i.e. the genetic substance of the bacteria, from being compacted like a twisted garden hose in space-saving manner," says Prof Rolf Müller, who is the Executive Director of the HIPS and the head of the Microbial Natural Products department and supervises the Novel Antibiotics research area of the DZIF. In the words of the president of Saarland University, Prof Manfred Schmitt, "the discovery of this novel class of drugs is additional compelling proof of the excellent and highly successful cooperation between the extra-mural partners HIPS and HZI and the University's research groups in pharmacy and the natural sciences at the Saarbrücken Campus."
The researchers see great potential in the chemical optimisation of the drug, in which the three research groups at the HIPS, the HZI and the Leibniz University Hannover are involved. "The chemical modification increased and broadened the activity against Gram-negative bacteria," Brönstrup says. Following on the heels of the initial investigations of structure-activity relationships by the research group of Prof Rolf Hartmann at the HIPS, a scalable synthesis of the optimised substance for industrial use was established by the research group of Prof Andreas Kirschning at the Leibniz University Hannover. "Cystobactamids are a great new hope in the fight against Gram-negative pathogens and they will be optimised with the goal to nominate a clinical candidate in our collaborative work with Evotec," Brönstrup says.
Initially, the cooperation of Evotec and the HZI in the scope of the new cooperation platform is scheduled for three years. The cooperation combines the unique collection of natural substances and the knowledge related to these substances as well as the access to in vitro and in vivo models of bacterial infections, contributed by the HZI, and Evotec's drug discovery and development platforms, the expertise in medicinal chemistry and pharmacology as well as their comprehensive collection of pathogenic bacteria.
Leibniz University Hannover:
Its nearly 30,000 students and approximately 170 courses of study with a broad spectrum of subjects ranging from the natural and engineering sciences to the liberal arts and social sciences, teacher education, economics and law make the LUH the second largest university in Lower Saxony. The interdisciplinary and international research focuses in biomedicine, mechanical engineering, quantum optics and gravitational physics are steadily being expanded. Its three excellence clusters successfully represent the LUH in the excellence strategy of the federal and state governments. www.uni-hannover.de
German Center for Infection Research:
At the German Center for Infection Research (DZIF), about 500 scientists from 35 institutions nationwide jointly develop new approaches for the prevention, diagnosis and treatment of infectious diseases. Their aim is to translate research results into clinical practice rapidly and effectively. With this, the DZIF paves the way for developing new vaccines, diagnostics and drugs in the fight against infections. Further information at: www.dzif.de
