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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 are interested in the characterization of thanatin-like drug candidates using solution NMR and biophysical methods to determine their pharmacological properties.

Lpt_structure.png

outer

membrane

inner

membrane

LptA

Thanatin

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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