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

Discovery of a Tricyclic β-Lactam as a Potent Antimicrobial Agent against Carbapenem-Resistant Enterobacterales, Including Strains with Reduced Membrane Permeability and Four-Amino Acid Insertion into Penicillin-Binding Protein 3: Structure–Activity-Relationships and In Vitro and In Vivo Activities

“…Encouraged by the identification of compound 1a, which showed potent activities against CREs in our previous work, 15 we continued advanced research on this series. The structure− activity relationships for several analogues with modified alkoxyimino moieties of the aminothiazole side chain are summarized in Table 1 by the MICs of six strains including two low susceptible strains described below.…”

“…1 H NMR (400 MHz, CDCl 3 ): δ 2.52 (2H, t, J = 3.1 Hz), 2.60 (1H, dd, J = 14.5, 9.6 Hz), 2.90 (1H, dd, J = 14.5, 4.5 Hz), 3.08−3.13 (1H, m), 3 15 (3aR,5S,5aR,6R,8aR) Evaluation of In Vitro Antibacterial Activity. The MICs were determined using the broth microdilution method in accordance with Clinical Laboratory Standards Institute guidelines.…”

“…We recently identified the novel tricyclic β-lactam 1a which has a γ-lactone ring and a sulfoxide of the tricyclic core as key structures for exhibiting potent antibacterial activities against several problematic β-lactamase-producing CREs without a BLI (Figure 1). 15 During the evaluation of 1a, two strains with increased MICs were found, and their characterization revealed that they are a porin-deficient strain and a four-amino acid inserted strain. We conducted further modifications of compound 1a aimed at overcoming these resistant mechanisms and improving its antibacterial activities.…”

Stereoselective Synthesis of Tricyclic β-Lactam by Sulfoxide-Directed Oxidative Lactonization from an Accessible Cephalosporin Intermediate

“…We recently identified tricyclic β-lactam 3 as a promising drug candidate for infectious diseases caused by CREs. , The structure of 3 is a merger of the third-generation cephalosporin ceftazidime ( 1 ) and a cycloserine natural product named lactivicin (LTV, 2 ) (Figure ). The unique tricyclic β-lactam exhibits potent antibacterial activities against several problematic β-lactamase-producing CREs without the use of β-lactamase inhibitors.…”

“…Scientists at Takeda synthesized 8 , an intermediate leading to 3 , by two transformations from penicillin in the 1980s: (a) ring opening and removal of the penam structure of 4 to form 5 and (b) reaction with 6 to construct the six-membered ring, which possesses functional groups enabling the third lactone cyclization (Scheme ). This route enabled us to commence our structure–activity relationship (SAR) effort, , but challenges remained for scale-up of the synthesis and sufficient supply of the intermediate for further backup SAR. The issues related to the synthesis of the key intermediate 8 were (a) the long route (eight linear steps) from penicillin G, (b) the use of the labile enone 6 , which easily isomerizes and polymerizes, and (c) the formation of undesired diastereomers of 7 .…”