Synergistic Antibacterial Activity of Meropenem and Imipenem in Combination with Diazabicyclooctane Derivatives

Abstract— The diazabicyclooctane (DBO) has emerged as the attractive motif for the development of new β-lactamase inhibitors after the clinical approval of avibactam and relebactam. We are striving at improving the lactamase inhibition strength and antibacterial spectrum of the DBO derivatives. We synthesized the substituted-amidine derivatives (5a–5j) of the DBO, and determined the antibacterial efficacy of the two β-lactam drugs i.e. imipenem and meropenem, in combination with compounds 5a–5j. All these derivatives lowered the MIC values of the imipenem and meropenem, indicating their β-lactamase inhibition profile, however in variable strength. The best results were obtained when the compounds 5a–5j were combined with meropenem indicating the better association of these compounds with meropenem in comparison to imipenem. With meropenem, compounds 5a and 5b proved to be the most potent exhibiting the highest antibacterial efficacy against five out of ten microbial strains. Moreover, the MIC data showed that β-lactamase inhibition strength of compounds 5a and 5b was comparable to relebactam in eight out of ten bacterial strains.