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Development of Novel Antibiotics

With the rise of multi-resistant bacteria, the need for novel antibiotics is increasingly urgent.  Lipopolysaccharide (LPS) is a hallmark antigen that coats the cell surface of most Gram-negative bacteria. The LPS transport (Lpt) machinery, which transports LPS across the periplasm to the outer membrane, is a novel target for a new class of antibiotics.


Thanatin, a natural antimicrobial peptide, disrupts the binding interfaces of Lpt proteins, ultimately functioning as a bactericidal agent. In collaboration with Polyphor, we developed peptides based on the thanatin scaffold, that are highly active in carbapenem-resistant Enterobacteriacaea (CRE). They are still very potent in mutidrug resistant Gram-negative hospital strains that cause so much trouble nowadays in therapy. They have drug-like  properties (stability in blood serum, low toxicity etc.). In particular they are demonstrated to only slowly build up new resistances, because they are still highly active against the most frequently occurring thanatin-resistant target mutant.

We are now working on adapting these molecules to other Gram-negative pathogens. In addition we study uptake of these peptides, and potential efflux mechanisms. Moreover, we are establishing the biochemistry on other players of the lipopolysaccharide transport bridge, to eventually enable a combination therapy against two components of the bridge.

The 2023 Science Advances paper triggered a for me so-far not experienced echo in the press, demonstrating that the development of novel antibiotics is of interest to many of us!


Key references

  • S. U. Vetterli, K. Zerbe, M. Müller, M. Urfer, M. Mondal, S.-Y. Wang, K. Moehle, O. Zerbe, A. Vitale, G. Pessi, L. Eberl, B. Wollscheid and J. A. Robinson: Thanatin Targets the Inter-Membrane Protein Bridge Required for Lipopolysaccharide Transport in Escherichia coli (2018) Science Advances, 4, eaau2634.

  • K. Moehle, H. Kocherla, B. Bacsa, S. Jurt, K. Zerbe, J. A. Robinson, O.Zerbe: Solution structure and dynamics of LptE from Pseudomonas aeruginosa, Biochemistry, 55 (2016), 2936-2943.

  • M. Schuster, E. Brabet, K.K. Oi, N. Desjonquères, K. Moehle, K. Le Poupon, S. Hell, S. Gable, V. Rithié, S. Dillinger, P. Zbinden, A. Luther, C. Li, S. Stiegeler, C. D’Arco, H. Locher, T. Remus, S. DiMaio, P. Motta, A. Wach, F. Jung, G. Upert, D. Obrecht, M. Benghezal, O. Zerbe, Peptidomimetic Antibiotics Disrupt the Lipopolysaccharide Transport Bridge of Drug-Resistant Enterobacteriaceae, Sci. Adv., 9 (2023), eadg368.

  • K. Oi, K. Moehle, M. Schuster, O Zerbe: Early molecular insights into thanatin analogues binding to A. baumannii LptA, Molecules, 28 (2023) , 4335.

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