Glycopeptide antibiotic candidate shows promise

Researchers from the University of Vienna and the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) have discovered a new type of glycopeptide antibiotic known as saarvienin A, found to have strong activity against highly resistant bacterial strains. Their work has been published in the journal Angewandte Chemie International Edition.

In the search for new antibiotic compounds, researchers have turned to the study of actinobacteria — microorganisms that are well-known for living in unusual environments and producing antibiotics such as vancomycin, rifamycin and chelocardin. Vienna’s Jaime Felipe Guerrero Garzón discovered strong antibiotic activity in extracts from a strain of Amycolatopsis isolated from a Chinese rare earth mine, which prompted further investigation.

Martin Zehl, Head of the Mass Spectrometry Centre at the University of Vienna, found out that the antibiotic activity was associated with a potentially novel compound of the class glycopeptides. Using mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, the collaborating team at HIPS identified a completely new molecule: saarvienin A.

Saarvienin A’s special feature became clear early on: unlike established glycopeptides such as vancomycin, the new compound does not bind the typical bacterial target involved in cell wall synthesis. Instead, it probably acts through a different, as yet unresolved mechanism. Structural analysis revealed a distinctive architecture: a halogenated peptide core cyclised through an unusual ureido linkage, decorated with a chain of five sugar and aminosugar units — two of which are completely new to natural products.

“We were excited to find that saarvienin A doesn’t fit into any known category,” Guerrero Garzón said. “Its unique structure could pave the way for antibiotics that bacteria have never encountered before.”

Researchers at HIPS characterised the biological activity of saarvienin A, named after the cities of Saarbrücken and Vienna. Tests of the new molecule against bacteria focused on ‘ESKAPE pathogens’ — a notorious group of superbugs known to evade most current antibiotics. The compound showed remarkable activity against vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus (MRSA), including 3 ESKAPE pathogens and 26 clinical isolates. It consistently outperformed vancomycin, even against strains already resistant to multiple other antibiotics.

With the biosynthetic genes for saarvienin A already identified and cloned, the researchers plan to use medicinal chemistry and biosynthetic engineering to optimise the molecule. A key goal is to reduce cytotoxicity while maintaining antibacterial activity.

“Discovering a new antibiotic is only the beginning,” said corresponding author Sergey B Zotchev, from the University of Vienna. “Now we face the fascinating challenge of refining it into a drug candidate suitable for clinical use.”

Image caption: NMR used for structural identification at HIPS. Image ©HIPS/Dietze.