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

Abstract

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.

Comparison of the Performance of Phenotypic Methods for the Detection of Carbapenem-Resistant Enterobacteriaceae (CRE) in Clinical Practice

“…So, CDT will fail to accurately pick up class D beta-lactamases. If a strain overexpresses a class C beta-lactamase and also has loss of porins or increased efflux it may test as a CRE ( Fujiu et al., 2021 ) and also be false positive on CDT with phenylboronic acid. The other probably for false positives on CDT is the limitation to which genes were detected via PCR/sequencing.…”

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…Alternatively, the carboxyl group in 17 was first esterified to form 28, and appropriate alkyl bromofluoroacetate was reacted to the benzyl deprotected intermediate to form the fluoroacetate derivatives 29. The individual compounds 29 were then subjected to photo-induced thiolation before saponification in R 2 to reach the final target compounds 31 (Schemes 6 and 7) [71]. This research group also prepared thio-substituted DBOs in which the N-hydroxy position of DBO was activated with fluoroacetate derivatives instead of sulfonic acid.…”

“…Alternatively, the carboxyl group in 17 was first esterified to form 28, and appropriate alkyl bromofluoroacetate was reacted to the benzyl deprotected intermediate to form the fluoroacetate derivatives 29. The individual compounds 29 were then subjected to photo-induced thiolation before saponification in R2 to reach the final target compounds 31 (Schemes 6 and 7) [71]. Triazole functionalized DBOs: Unsubstituted and several triazole ring-substituted DBO derivatives (Scheme 8) were synthesized for inhibition against TEM-1, KPC-2, CTX-M-15, AmpC, and OXA-48 BLAs in vitro.…”

Copper-Catalyzed C–S Formation for the Synthesis of Benzyl Phenyl Sulfides from Dithiocarbamates

“…13 C NMR (100 MHz, CDCl3, TMS): δ (ppm) = 135. 6,132.9,131.7,130.4,129.1,127.8,127.7,127.2,126.3,125.4,125.1,124.8,124.2,122.8,sulfide (3m) [18g] :…”

“…a, b) and their oxidative products also show great antimicrobial value. [6] Figure 1. Representative biologically active compounds containing benzyl phenyl sulfides skeletons.…”