Discovery of 2-Sulfinyl-Diazabicyclooctane Derivatives, Potential Oral β-Lactamase Inhibitors for Infections Caused by Serine β-Lactamase-Producing Enterobacterales

Coadministration of beta-lactam and beta-lactamase inhibitor (BLI) is one of the well-established therapeutic measures for bacterial infections caused by beta-lactam-resistant Gram-negative bacteria, whereas we have only two options for orally active BLI, clavulanic acid and sulbactam. Furthermore, these BLIs are losing their clinical usefulness because of the spread of new beta-lactamases, including extended-spectrum beta-lactamases (ESBLs) belonging to class A beta-lactamases, class C and D beta-lactamases, and carbapenemases, which are hardly or not inhibited by these classical BLIs. From the viewpoints of medical cost and burden of healthcare personnel, oral therapy offers many advantages. In our search for novel diazabicyclooctane (DBO) BLIs possessing a thio-functional group at the C2 position, we discovered a 2-sulfinyl-DBO derivative (2), which restores the antibacterial activities of an orally available third-generation cephalosporin, ceftibuten (CTB), against various serine beta-lactamase-producing strains including carbapenem-resistant Enterobacteriaceae (CRE). It can be orally absorbed via the ester prodrug modification and exhibits in vivo efficacy in a combination with CTB.

Automated summary

The discovery of an orally absorbed novel antibiotic with good antibacterial activity against resistant strains may be a promising option for treating bacterial infections.