Using optimised natural products against difficult pathogens

Improved darobactin derivatives show activity against carbapenem-resistant hospital germs

Combined with a growing human population and the increasing problem of antimicrobial resistance (AMR) in bacteria, healthcare systems are facing a global antibiotic crisis. To effectively combat AMR, new antibiotics with new mechanisms of action are needed more urgently than ever before. A team led by Rolf Müller from the Department of Microbial Natural Products has now further optimised the natural product class of darobactins, which was discovered in 2019, and the developed frontrunner shows promising properties against the carbapenem-resistant hospital pathogen Acinetobacter baumannii and other clinically relevant pathogens.

The natural product darobactin was isolated from the bacterium Photorhabdus khanii and proves to be very active not only in vitro but also in vivo. One of the advantages for human application is that this class of compounds is not active against commensal intestinal bacteria from the Bacteriodes family. Through structure-based optimisation, the team has now succeeded in developing a candidate with very good activity, which so far shows no significant signs of toxic side effects. In the video, Carsten explains more about the work, which was published in the journal Angewandte Chemie.

Original Publication:

Seyfert, C.E., Porten, C., Yuan, B., Deckarm, S., Panter, F., Bader, C.D., Coetzee, J., Deschner, F., Tehrani, K.H.M.E., Higgins, P.G., Seifert, H., Marlovits, T.C., Herrmann, J. and Müller, R. (2022) Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering, Angew. Chem. Int. Ed., 10.1002/anie.202214094

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