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1.
EMBO Mol Med ; 16(5): 1051-1062, 2024 May.
Article in English | MEDLINE | ID: mdl-38565805

ABSTRACT

The emergence of drug-resistant Enterobacteriaceae carrying plasmid-mediated ß-lactamase genes has become a significant threat to public health. Organisms in the Enterobacteriaceae family containing New Delhi metallo-ß-lactamase­1 (NDM-1) and its variants, which are capable of hydrolyzing nearly all ß-lactam antibacterial agents, including carbapenems, are referred to as superbugs and distributed worldwide. Despite efforts over the past decade, the discovery of an NDM-1 inhibitor that can reach the clinic remains a challenge. Here, we identified oxidized glutathione (GSSG) as a metabolic biomarker for blaNDM-1 using a non-targeted metabolomics approach and demonstrated that GSSG supplementation could restore carbapenem susceptibility in Escherichia coli carrying blaNDM-1 in vitro and in vivo. We showed that exogenous GSSG promotes the bactericidal effects of carbapenems by interfering with intracellular redox homeostasis and inhibiting the expression of NDM-1 in drug-resistant E. coli. This study establishes a metabolomics-based strategy to potentiate metabolism-dependent antibiotic efficacy for the treatment of antibiotic-resistant bacteria.


Subject(s)
Anti-Bacterial Agents , Carbapenems , Escherichia coli , Glutathione , beta-Lactamases , beta-Lactamases/metabolism , beta-Lactamases/genetics , Escherichia coli/genetics , Escherichia coli/drug effects , Carbapenems/pharmacology , Anti-Bacterial Agents/pharmacology , Animals , Glutathione/metabolism , Microbial Sensitivity Tests , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Mice , Metabolomics , Oxidation-Reduction/drug effects , Humans
3.
Microbiol Spectr ; 9(2): e0062521, 2021 10 31.
Article in English | MEDLINE | ID: mdl-34612668

ABSTRACT

Metabolomics is a powerful tool that can systematically describe global changes in the metabolome of microbes, thus improving our understanding of the mechanisms of action of antibiotics and facilitating the development of next-generation antibacterial therapies. However, current sample preparation methods are not efficient or reliable for studying the effects of antibiotics on microbes. In the present study, we reported a novel sample preparation approach using cold methanol/ethylene glycol for quenching Escherichia coli, thus overcoming the loss of intracellular metabolites caused by cell membrane damage. After evaluating the extraction efficiency of several extraction methods, we employed the optimized workflow to profile the metabolome of E. coli exposed to cephalexin. In doing so, we proved the utility of the proposed approach and provided insights into the comprehensive metabolic alterations associated with antibiotic treatment. IMPORTANCE The emergence and global spread of multidrug-resistant bacteria and genes are a global problem. It is critical to understand the interactions between antibiotics and bacteria and find alternative treatments for infections when we are moving closer to a postantibiotic era. It has been demonstrated that the bacterial metabolic environment plays an important role in the modulation of antibiotic susceptibility and efficacy. In the present study, we proposed a novel metabolomic approach for intracellular metabolite profiling of E. coli, which can be used to investigate the metabolite alterations of bacteria caused by antibiotic treatment. Further understanding of antibiotic-induced perturbations of bacterial metabolism would facilitate the discovery of new therapeutic targets and pathways.


Subject(s)
Escherichia coli/metabolism , Metabolome , Metabolomics/methods , Anti-Bacterial Agents/pharmacology , Bacteria/metabolism , Cell Membrane/drug effects , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Ethylene Glycol/pharmacology , Transcriptome
4.
Food Chem ; 365: 130502, 2021 Dec 15.
Article in English | MEDLINE | ID: mdl-34252621

ABSTRACT

A simple and reliable analytical method was developed for the simultaneous determination of 11 macrolides in swine, chicken, bovine, and sheep tissues (muscle, liver, kidney, and fat), as well as eggs. Samples were extracted using a mixture of acetonitrile, ethyl acetate, and methanol; dispersive solid-phase extraction purification was then performed using multi-walled carbon nanotubes as the sorbent. The analytes were separated through ultra-high performance liquid chromatography and detected by electrospray ionization on a triple quadrupole mass spectrometer. The average recoveries ranged from 83.5% to 111.4%; the corresponding intra-day and inter-day relative standard deviations were less than 13.6% and 16.4%, respectively. The limit of detection and quantification of the eggs were 0.1-0.6 and 2.0 µg/kg, respectively. For other tissues, the limits of detection and quantification were 0.1-2.0 µg/kg and 5.0 µg/kg, respectively. The proposed method was successfully employed for the analysis of real samples to demonstrate its applicability.


Subject(s)
Nanotubes, Carbon , Animals , Cattle , Chromatography, High Pressure Liquid , Macrolides , Sheep , Solid Phase Extraction , Swine , Tandem Mass Spectrometry
5.
Environ Int ; 155: 106651, 2021 10.
Article in English | MEDLINE | ID: mdl-34033976

ABSTRACT

The occurrence of 187 pharmaceuticals and personal care products (PPCPs) was investigated in bottled water samples (35 and 33 from Chinese and foreign brands, respectively). Forty-four compounds belonging to 14 PPCP categories were detected in 56 of the 68 bottled water samples. Further, more than 35% of water samples contained at least three PPCPs, and in one particular sample, 11 different PPCPs were detected. Macrolides constituted the most prevalent PPCP category, and salbutamol, erythromycin, and azithromycin showed the highest detection frequency (17.6%). The thermal stabilities of the 187 PPCPs were determined, and the results obtained showed that only 35 out of the 187 compounds were degraded by more than 50% after boiling for 5 min. Even though the risk quotients (RQs) of detected PPCPs showed low risk levels, the RQs of 13 compounds with RQs ≥ 0.0001 were 2-4 fold higher in infants than in other life stages. Moreover, further studies are necessary to evaluate the toxicity of PPCP mixtures, the effects of PPCPs on human intestinal microbiota, and their risk of induction of drug-resistant bacteria and drug-resistant genes.


Subject(s)
Cosmetics , Drinking Water , Pharmaceutical Preparations , Water Pollutants, Chemical , Cosmetics/analysis , Environmental Monitoring , Humans , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/toxicity
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