Abstract
BackgroundExtended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae poses serious challenges to clinicians because of its resistance to many classes of antibiotics.Methods and FindingsThe mechanism of synergistic activity of a combination of (−)-epigallocatechin-3-gallate (EGCG) and β-lactam antibiotics cefotaxime was studied on Extended-spectrum β-lactamase producing Escherichia coli (ESBL-EC), by visualizing the morphological alteration on the cell wall induced by the combination using atomic force microscopy (AFM). Cells at sub-MICs (sub-minimum inhibitory concentrations) of cefotaxime were initially filamentated but recovered to the normal shape later, whereas cells at sub-MICs of EGCG experienced temporal disturbance on the cell wall such as leakage and release of cellular debris and groove formation, but later recovered to the normal shape. In contrast, the combination of cefotaxime and EGCG at their respective sub-MICs induced permanent cellular damages as well as continuous elongation in cells and eventually killed them. Flow cytometry showed that intracellular oxidative stress levels in the cell treated with a combination of EGCG and cefotaxime at sub-MICs were higher than those in the cells treated with either cefotaxime or EGCG at sub-MICs.ConclusionsThese results suggest that the synergistic effect of EGCG between EGCG and cefotaxime against ESBL-EC is related to cooperative activity of exogenous and endogenous reactive oxygen species (ROS) generated by EGCG and cefotaxime, respectively.
Highlights
These results suggest that the synergistic effect of EGCG between EGCG and cefotaxime against Extended-spectrum b-lactamase (ESBL)-EC is related to cooperative activity of exogenous and endogenous reactive oxygen species (ROS) generated by EGCG and cefotaxime, respectively
The reemergence of infectious diseases and the continuous development of antimicrobial drug resistance in pathogens have been causing an alarming deficit in effective antibacterial agents, leading to a growing threat to public healthcare worldwide
ESBLs are the enzymes produced by Gram-negative bacteria that mediate resistance to third-generation cephalosporins by hydrolysis of these antibiotics [2]
Summary
The reemergence of infectious diseases and the continuous development of antimicrobial drug resistance in pathogens have been causing an alarming deficit in effective antibacterial agents, leading to a growing threat to public healthcare worldwide. Extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae have become the most frequent nosocomial pathogens and have posed serious challenges to clinicians because of their resistance to many classes of antibiotics [1]. ESBLs are the enzymes produced by Gram-negative bacteria that mediate resistance to third-generation cephalosporins (such as cefotaxime and ceftriaxone) by hydrolysis of these antibiotics [2]. Combinations of a b-lactam with either a b-lactamase inhibitor or a fluoroquinolone, or double b-lactam combinations are common, but these may not always prevent the emergence of resistance [4], [5]. Extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae poses serious challenges to clinicians because of its resistance to many classes of antibiotics
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