A novel tricyclic β-lactam exhibiting potent antibacterial activities against carbapenem-resistant Enterobacterales: Synthesis and structure-activity-relationships

A series of tricyclic beta-lactams were synthesized and evaluated for in vitro antibacterial activities against carbapenem-resistant Enterobacterales (CBEs). Starting from a reported tricyclic beta-lactam that combined the cephalosporin skeleton having a gamma-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic beta-lactam also shows a strong therapeutic efficacy in the neutmpenic mouse lung infection model. These results indicate that the tricyclic beta-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new antibacterial agents against CREs.

Automated summary

A series of tricyclic beta-lactams were synthesized and evaluated for antibacterial activities against carbapenem-resistant Enterobacterales (CBEs). Introducing sulfoxide resulted in potent antibacterial activities and strong therapeutic efficacy in a neutropenic mouse lung infection model. The tricyclic beta-lactam skeleton may serve as a promising scaffold for new antibacterial agents against CREs.