OP0595, a new diazabicyclooctane: mode of action as a serine ß-lactamase inhibitor, antibiotic and ß-lactam 'enhancer'.

OBJECTIVES: The production of a growing diversity of ß-lactamases by Gram-negative bacteria challenges antimicrobial chemotherapy. OP0595, discovered separately by each of Meiji Seika Pharma and Fedora Pharmaceuticals, is a new diazabicyclooctane serine ß-lactamase inhibitor that also acts as an antibiotic and as a ß-lactamase-independent ß-lactam 'enhancer'. METHODS: Inhibitory activity against serine ß-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with ß-lactam agents were measured according to CLSI recommendations. Morphological changes in Escherichia coli were examined by phase-contrast microscopy. RESULTS: IC50s of OP0595 for class A and C ß-lactamases were <1000 nM, with covalent binding demonstrated to the active-site serine of CTX-M-44 and AmpC enzymes. OP0595 also had direct antibiotic activity against many Enterobacteriaceae, associated with inhibition of PBP2 and conversion of the bacteria into spherical forms. Synergy between OP0595 and ß-lactam agents was seen against strains producing class A and C ß-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner ß-lactam agents for a non-ß-lactamase-producing E. coli mutant that was resistant to OP0595 itself, indicating ß-lactamase-independent 'enhancer'-based synergy. CONCLUSIONS: OP0595 acts in three ways: (i) as an inhibitor of class A and C ß-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an 'enhancer' of ß-lactam agents that bind to other PBPs besides PBP2 for several Enterobacteriaceae. OP0595 has considerable potential to overcome resistance when it is combined with various ß-lactam agents.

Ring-expansion reaction of oximes with aluminum reductants.

The ring-expansion reactions of heterocyclic ketoximes and carbocyclic ketoximes with several reductants such as AlHCl2, AlH3 (alane), LiAlH4, LiAlH(OtBu)3, and (MeOCH2CH2O)2AlH2Na (Red-Al) were examined. Among reductants, AlHCl2 (LiAlH4:AlCl3 = 1:3) in cyclopentyl methyl ether (CPME) has been found to be a suitable reagent for the reaction, and the rearranged cyclic secondary amines were obtained in good to excellent yields.

Total synthesis of PDE-II by copper-mediated double amination.

A concise total synthesis of PDE-II featuring copper-mediated double aryl amination with the combination of CuI, CsOAc, and Cs2CO3 is described. The highly substituted pyrroloindole skeleton was constructed by a one-pot five-step sequence including double aryl amination, beta-elimination, deprotection of a Cbz group, and removal of an Ns group followed by rearomatization.