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Evaluation of inhibitory effects of racemic and enantiomerically pure N-benzyl-3-amidoquinuclidinim salts against extended spectrum β-lactamase-producing pathogens

Over the past decade, the widespread emergence of antibiotic resistant bacterial pathogens has resulted in a worldwide crisis. Inspired by their diverse biological activity of quinuclidine based structures, we have synthesized various enantiomeric forms and characterized class of Nbenzyl-3-amidoquinuclidinium salts to select a potent of antimicrobial agents as well as β- lactamase inhibitors. The antibacterial activity was evaluated against 18 recent clinical isolates of antibioticsusceptible Gram-positive and resistant Gram-negative pathogens by determining their zone of inhibition and minimum inhibitory concentrations. The bioactive assay showed that some of enantiomer displayed comparable or even better antibacterial efficacy in comparison with standard antibiotics. More interestingly, that target compounds are not only active against antibiotic susceptible Gram-positive bacteria, but also exhibit significant antibacterial effects against Gram-negative isolates with various antibiotic resistance profiles. The antimicrobial efficacies of N-benzyl-3-amidoquinuclidinium salts highlight the significance of stereochemistry in antimicrobial activity. The most active compound Q5 showed the lowest MIC value of 6.25 μg/mL against all Gram-negative bacteria. We further show that compound Q5 has the ability to restore antibacterial activity against ten multidrug isolates that express a wide range of β- lactamase enzymes of classes A and C. By fluorescence microscopy it was revealed that compounds Q5 interact with the negatively charged bacterial cell membrane and disrupt the membrane integrity. The cytotoxicity of compound Q5 was determined by assessing viability of human embryonic kidney (HEK293T) cell line by MTT assay. Bacterial kinetic growth after treatment was measured by quantifying cell viability at 0, 2, 4, 6, and 24 h after incubation with different concentrations of compound Q5 using time-kill assays. Our preliminary results showed that this compound has no cytotoxicity against HEK293T cells. These results may lead to development a new class of antimicrobial could potentially function as novel therapeutics to help combat antibiotic resistance.

3-amidoquinuclidinium salts ; beta-lactamase inhibitors ; cytotoxicity ; fluorescence microscopy

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