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

Abstract

The current worldwide emergence of carbapenem-resistant enterobacterales (CREs) constitutes an important growing clinical and public health threat. Acquired carbapenemases are the most important determinants of resistance to carbapenems. In the development of the previously reported tricyclic β-lactam skeleton which exhibits potent antibacterial activities against several problematic β-lactamase-producing CREs without a β-lactamase inhibitor, we found that these activities were reduced against clinical isolates with resistance mechanisms other than β-lactamase production. These mechanisms were the reduction of outer membrane permeability with the production of β-lactamases and the insertion of four amino acids into penicillin-binding protein 3. Here, we report the discovery of a potent compound that overcomes these resistance mechanisms by the conversion of the alkoxyimino moiety of the aminothiazole side chain in which a hydrophilic functional group is introduced and the carboxylic acid of the alkoxyimino moiety is converted to reduce the negative charge of the whole molecule from 2 to 1. This potent tricyclic β-lactam is a promising drug candidate for infectious diseases caused by CREs due to its potent therapeutic efficacy in the neutropenic mouse lung infection model and low frequency of producing spontaneously resistant mutants.

The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

“…Woodward ( Ernest et al, 1978 ). The penem class is one of a few β-lactam antibiotics still being researched, and includes faropenem, ritipenem, and sulopenem ( Batchelder et al, 2020 ; Butler et al, 2022 ; Sato et al, 2022 ). While no members of the thiapenem class are currently used in United States clinical settings, safety and efficacy data required for FDA approval are forthcoming.…”

Carbapenem antibiotic stress increases blaKPC‐2 gene relative copy number and bacterial resistance levels of Klebsiella pneumoniae

“…Compared to CR‐KP isolates grown on LB plates, not all nine isolates exhibited elevated carbapenem resistance, only five CR‐KP isolates exhibited elevated MICs to imipenem, from 32 μg/ml to 64 μg/ml or 64 μg/ml to 128 μg/ml, while the other four exhibited unchanged MICs to imipenem. Due to the methodological shortcomings of the broth microdilution method itself, with a large inter‐well span, we were unable to obtain exact MIC values, but it is not difficult for us to find that moderate antibiotic pressure can increase the MIC levels of CR‐KP to imipenem, and this also suggests that KPC enzymes alone are not always sufficient to confer carbapenem resistance, but that multiple resistance mechanisms coexist (production of carbapenem hydrolases, 38–40 reduction of carbapenem membrane permeability, 41 loss of bacterial channel proteins, 42 overexpression of bacterial active efflux systems, 43 etc.). For example, the copy number of strain 5 in this study was relatively low, but its drug resistance level reached 256 μg/ml.…”

Penicillin-binding protein (PBP) inhibitor development: A 10-year chemical perspective

“…30 Resistance in Gram-negative organisms is multicausal and includes reduction of outer membrane permeability, caused by porin deficiency, as well as β-lactamase production and degradation of target affinity through the introduction of mutations in PBPs. 31 Cefiderocol (4), formerly known as S-649226, is a siderophore with a cephalosporin core (5, Figure 3) developed by Shionogi & Co., Ltd. [32][33][34] to treat infections caused by carbapenem-resistant Gram-negative bacteria. The compound has already been approved in the United States and Europe for the treatment of infections in adults.…”