Novel Synthetic Derivatives of Dichloroimidazole Targeting NorA Efflux Pump against Methicillin-Resistant Staphylococcus aureus

Abstract

Introduction: Antibiotic resistance has been a major health problem in recent years, which has led to a failure in the treatment of infectious diseases. Therefore, research to synthesize compounds that have antibiotic activity is very valuable. In present study four novel compounds (6a-d) , derivatives of dichloroimidazole conjugated with triazole, were synthesized in order to obtain new bacterial efflux pump inhibitors (EPIs). Methods and Results: The derivatives were evaluated for their effects on the minimum inhibitory concentration (MIC) of ciprofloxacin against a methicillin and ciprofloxacin resistant Staphylococcus aureus (MCRSA) clinical isolate. Based on broth microdilution method assay, four derivatives at a minimum effective concentration (MEC) fortified the antibacterial efficacy of ciprofloxacin against MCRSA. MIC of ciprofloxacin decreased in the presence of novel compounds compared to ciprofloxacin alone between 2 to 64 fold. These compounds were then evaluated for their potency as efflux pump inhibitors using a fluorometric assay. Results indicated an increase in accumulation of ethidium bromide (a known fluorescent substrate for the NorA pump) in the presence of each compound, like verapamil (a typical inhibitor of efflux pump), thus these compounds acted as inhibitors of the NorA pump. Moreover, the MTT assay confirmed that novel compounds did not demonstrate any cytotoxic effect against three cancer cell lines, HT-29, MCF-7 and Caco-2, and a normal mouse fibroblastic cell line, NIH-3T3. Conclusion: Collectively, our results propose these derivatives as therapeutic options in combination therapies to tackle antibiotic resistance. Key words: Synthesis, Triazoles, Antibacterial activity, Cytotoxic activity, Inhibitors Grants: This research has been supported by Grant Number 94-02-33-29506 from Deputy of Research, Tehran University of Medical Science.