The ADvANCE project, funded by the German Federal Ministry of Education and Research (BMBF) under the grant number 16GW0215K, ran from 1 April 2019 to 31 March 2023. It was carried out by the Institute for Medical Microbiology, Immunology and Hygiene at the Technical University of Munich (TUM) in close collaboration with the Heidelberg University Medical Center (HMGU). TUM coordinated the overall effort, performed biochemical and biological activity assays, and managed external synthesis and ADME‑toxicity studies, while HMGU supplied the initial fragment libraries and a patented AI‑driven design platform that analyzes 20 000 protein‑inhibitor structures to suggest chemical modifications.
The scientific focus was the development of natural‑product‑derived fragments that inhibit carbapenemases, the enzymes responsible for resistance to the last‑resort β‑lactam antibiotics. Two fragment classes were identified: one from the HMGU library that blocks both serine‑β‑lactamases (SBL) and metallo‑β‑lactamases (MBL), and a second derived from a natural product that selectively inhibits several MBL enzymes. Chemical optimisation guided by the AI platform led to derivatives with markedly improved inhibition of individual carbapenemases, as demonstrated in both in‑vitro enzymatic assays and bacterial growth inhibition tests. Although none of the new compounds achieved broad‑spectrum potency across all tested carbapenemases, the enhanced activity against specific targets was confirmed biochemically and biologically. In addition, the non‑natural‑product fragment class displayed intrinsic antibacterial activity, suggesting a dual mode of action.
Attempts to strengthen β‑lactamase inhibitor (BLI) activity were largely modest; improvements were limited to single enzymes. The emergence of boronate BLIs such as Taniborbactam and QPX7728, both in clinical trials (Phase I and Phase III respectively), highlighted the high performance of this class and shifted the field’s interest toward directly active antibiotics. Consequently, the ADvANCE team redirected efforts toward antibacterial efficacy, leveraging the freedom‑to‑operate status of the fragment class.
The project’s outcomes enabled the acquisition of two additional funding streams—m4 Award and GO‑Bio initial at TUM—which further advanced antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. These grants also supported team expansion and sustained expertise. Through visibility in these programmes, contacts were established with INCATE and ENABLE‑2, providing strategic guidance, and with several investors who may support a future spin‑off.
A key publication resulting from the work appeared in 2020: “Structure and Molecular Recognition Mechanism of IMP‑13 Metallo‑β‑Lactamase” in *Antimicrobial Agents and Chemotherapy*. The team is preparing a patent application for a new class of broad‑spectrum BLIs and will publish the associated findings once the filing is complete. Overall, the ADvANCE project delivered a deeper understanding of carbapenemase inhibition by natural‑product fragments, demonstrated improved potency against selected targets, and laid the groundwork for future antibacterial development and potential commercial exploitation.