engleski

Discovery of novel imidazolium oximes as modulators for extended-spectrum β-lactamases-induced multidrug resistance in Gram-negative bacteria

The continuous emergences of multidrug-resistant Gram-negative bacterial pathogens compromise the successful treatment of serious clinical infections and call for the discovery and development of new antimicrobials agents. Potential to overcome the existing antibiotic resistance mechanisms have to be shown by new antibiotic in the discovery phase. In an effort to develop highly potent new class antibacterial agents which can restore β-lactam efficacy against Gram-negative bacterial strains producing multiple β-lactamases, new oxime compounds were designed. All new N-substituted imidazolium oximes and their monoquaternary salt were synthesized and their structure was confirmed by elemental analysis and spectral studies (IR, 1H and 13C NMR. Preliminary screening against a panel of representative Gram-positive and Gram-negative bacteria including multidrug resistant bacterial strains by the disc diffusion as well as broth microdilution assays was performed. Based on the preliminary results we discovered several compounds that demonstrated potent in vitro activity against tested microorganisms with MIC values from 6.25 to 50.0 μg mL-1. Additionally, we then used the broth microdilution assay to investigate the antiresistance efficacy of most potent compounds against ten molecularly determined extended-spectrum β- lactamase (ESBL) producing strains in comparison to eight clinically relevant antibiotics. Separate chemical-species interaction for each antimicrobial drug revealed species-specific effects elicited by a majority of the treatments explored. Among compounds tested mchlorobenzyl and 4-butenyl substituents on the imidazole ring displayed promising broadspectrum antibacterial activity against Gram-negative bacterial strains. The screen generated one promising compound exhibited remarkable, antiresistance efficacy against a wide range of β-lactamases was obtained for Escherichia coli and Enterobacter cloacae producing multiple from A and C molecular classes which was 32-fold and 128-fold more potent than ceftazidime and cefotaxime, respectively, which leads to the suggestion that may be interesting candidate for further development of new antimicrobials to restore antibacterial activity particularly among multidrug Gram-negative β-lactamase expressing bacterial pathogens.

imidazolium oxime ; antimicrobial activity ; extended-spectrum β-lactamase (ESBL) ; multidrug resistance

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