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Pyridine-4-aldoxime and its qutaernary salts as modulators for extended spectrum beta- lactamase-producing pathogens

Antibiotic resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. However, the -lactam drug class, once the foundation of treatment regimens for many hospital and community acquired infections, is rapidly becoming obsolete due to the proliferation of - lactamases. To combat infection small molecules based on oxime scaffold have been developed as promising antimicrobial agent. The aim of the current study was to investigate antimicrobial profile and relationship between antimicrobial activity and structure of quaternized 4- pyridinium oxime with diverse substituents introduced into the benzyl ring to gain a better understanding of their mehanism of action. Their antimicrobial activity, kinetics, and molecular mechanism against a 14 clinically relevant bacteria, including multi-drug resistant Gram-positive and Gram-negative pathogenic bacteria were investigated in this study using multiple methods. The obtained results are very are very promising since many of the compounds demonstrated potent in vitro activity against a broad range of clinically important Gram-negative and Gram-positive bacteria, including multidrug resistant strains with MIC values from 0.48 to 125.0 μg mL-1. Structure-activity relationship analysis established that the best activities were obtained with Br and CH3 groups placed at into the benzyl ring. The inhibitory properties of oxime derivatives were measured across a wide variety of enzymes selected for their clinical relevance. Of the class A enzymes two enzymes were profiled: the widely disseminated extended-spectrum -lactamase CTX-M-15 and within class C the enzymes were chosen to represent Enterobacteriaceae with the AmpC from Enterobacter cloacae. Checkerboard assays was indicating that the combinations with ceftazidime and cefotaxime and compound with Br as p-substituent on benzyl ring showed the most potent synergistic inhibitory activity. This class of compounds could lead to an appealing class of antimicrobial agents combating multidrug resistant bacterial strains.

pyridine-4-aldoxime, quaternary salts, beta-lactamase

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