Abstract
The diazabicyclooctane (DBO) scaffold is the backbone of non-β-lactam-based second generation β-lactamase inhibitors. As part of our efforts, we have synthesized a series of DBO derivatives A1–23 containing amidine substituents at the C2 position of the bicyclic ring. These compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in vitro. All compounds did not show antibacterial activity when tested alone (MIC >64 mg/L), however, they exhibited a moderate inhibition activity in the presence of meropenem by lowering its MIC values. The compound A12 proved most potent among the other counterparts against all bacterial species with MIC from <0.125 mg/L to 2 mg/L, and is comparable to avibactam against both E. coli strains with a MIC value of <0.125 mg/L.
Highlights
Survival stress posed by antimicrobial agents triggers multiple mechanisms [1] in microorganisms leading to the initiation of antibiotic resistance and survival of the microorganisms [2]
In case of Gram-negative pathogenic bacteria, production of β-lactamases [3] is the main arsenal of these microorganisms against antibiotics
The minimum inhibitor concentration (MIC) values of MER without avibactam were observed to be in the range of 2 mg/L to 4 mg/L, whereas after the addition of avibactam the antibacterial activity changed to
Summary
Survival stress posed by antimicrobial agents triggers multiple mechanisms [1] in microorganisms leading to the initiation of antibiotic resistance and survival of the microorganisms [2]. This discovery led the researchers to develop second generation β-lactamase inhibitors, succeeded with the approval of avibactam and relebactam as non-β-lactam-based BLIs. Avibactam proved potent as inhibitor of Klebsiella pneumoniae carbapenemases (KPCs), AmpCs and some of class D β-lactamases [18] is in clinical practice in combination with ceftazidime [6].
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