Patrizio Mattei is a Distinguished Scientist, Medicinal Chemistry at the Roche Innovation Center Basel. Before joining Roche in 1999, he earned a Doctor of Sciences degree from the ETH Zürich and was a postdoctoral research fellow at The Scripps Research Institute in La Jolla, California.

Presentation Title: Discovery and process development of the new Antibiotic Zosurabalpin

Abstract: Zosurabalpin is the first representative of a structurally distinct compound class of antibiotics, which has
many features that position it to be a medical breakthrough. The first part of the talk will present its
optimization from a phenotypic HTS hit. Zosurabalpin is a tethered macrocyclic peptide, currently in
phase 1 clinical trials. It kills specifically Acinetobacter baumannii by blocking the trafficking of
lipopolysaccharide, a protein target that is unique to gram-negative bacteria. [1,2]
In the second part, the current state of development of the manufacturing process of the drug
substance will be discussed. A significant improvement of the output and robustness of the process was
obtained, by simplifying operations and changing reaction conditions in two key steps of the process
(the macrolactamization and the Suzuki coupling steps). Furthermore, replacing diethylamine with
dimethylbarbituric acid in the cleavage of the protecting groups (step 4) allowed a 5-fold reduction in
catalyst loading in that step, while also improving the purity profile of the intermediate, despite
significantly lower loading of the reagent.

[1] C. Zampaloni, P. Mattei, K. Bleicher et al., Nature 2024, 625, 566-571.
[2] K. S. Pahil, M. S. A. Gilman, V. Baidin et al., Nature 2024, 625, 572-577.

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