Asymmetric Synthesis of New β-Lactam Lipopeptides as Bacterial Signal Peptidase I Inhibitors

The transmembrane bacterial enzyme, signal peptidase I, is recognized as being a promising target for reducing the emergence of drug resistance. The asymmetric synthesis and the biological evaluation of original β‐lactam lipopeptides have been performed to discover potent signal peptidase inhibitors. The importance of the azetidinone motif of these lipopeptides has been demonstrated and can serve as a starting point to exploit and improve the reactivity of the β‐lactam in peptidomimetics. We present the design, asymmetric synthesis, and biological evaluation of novel β‐lactam lipopeptides, inhibitors of the signal peptidase I, an essential bacterial enzyme for the viability of both Gram‐negative and Gram‐positive bacteria. The importance of the azetidinone moiety is demonstrated and can serve as a starting point to improve the structure of these new kinds of SPase I inhibitors.