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

Coadministration
of β-lactam and β-lactamase inhibitor
(BLI) is one of the well-established therapeutic measures for bacterial
infections caused by β-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 β-lactamases, including
extended-spectrum β-lactamases (ESBLs) belonging to class A
β-lactamases, class C and D β-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 β-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.