Frontiers in Microbiology
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2024
·
IF 4
Sun Feifei,Zhang Lin,Ma Xuan,Ali Tariq,Wu Yongning,Li Lin
The emergence and widespread of tigecycline resistance undoubtedly poses a serious threat to public health globally. The exploration of combination therapies has become preferred antibacterial strategies to alleviate this global burden. In this study, tigecycline-resistant tet(X4)-positive Escherichia coli were selected for adjuvant screening. Interestingly, 9-aminominocycline (9-AMC), one of the tigecycline metabolites, exhibits synergistic antibacterial activity with tigecycline using checkerboard assay. The efficacy in vitro and in vivo was evaluated, and the synergistic mechanism was further explored. The results suggested that 9-AMC combined with tigecycline could inhibit the growth of antibiotic resistant bacteria, efficiently retard the evolution of tet(X4) gene and narrow the drug mutant selection window. In addition, the combination of tigecycline and 9-AMC could destroy the normal membrane structure of bacteria, inhibit the formation of biofilm, remarkably reduce the level of intracellular ATP level, and accelerate the oxidative damage of bacteria. Furthermore, 9-AMC is more stable in the bind of Tet(X4) inactivating enzyme. The transcriptomics analysis revealed that the genes related to the 9-AMC and tigecycline were mainly enriched in ABC transporters. Collectively, the results reveal the potentiation effects on tigecycline and the probability of 9-AMC as a novel tigecycline adjuvant against tet(X4)-positive Escherichia coli, which provides new insights for adjuvant screening.
研究领域:
微生物学
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药理学
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传染病学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Xinxin Jiang,Jingfei Long,Yanzhen Song,Xiaoyu Qi,Ping Li,Kuiquan Pan,Chenyang Yan,Hongzhou Xu,Haixia Liu
The transmission of antibiotic resistance genes (ARGs) in pathogenic bacteria affects culture animal health, endangers food safety, and thus gravely threatens public health. However, information about the effect of disinfectants - triclosan (TCS) on ARGs dissemination of bacterial pathogens in aquatic animals is still limited. One Citrobacter freundii ( C. freundii ) strain harboring tet (X4)-resistant plasmid was isolated from farmed grass carp guts, and subsequently conjugative transfer frequency from C. freundii to Escherichia coli C600 ( E. coli C600) was analyzed under different mating time, temperature, and ratio. The effect of different concentrations of TCS (0.02, 0.2, 2, 20, 200 and 2000 μg/L) on the conjugative transfer was detected. The optimum conditions for conjugative transfer were at 37 °C for 8h with mating ratio of 2:1 or 1:1 ( C. freundii : E. coli C600). The conjugative transfer frequency was significantly promoted under TCS treatment and reached the maximum value under 2.00 μg/L TCS with 18.39 times that of the control group. Reactive oxygen species (ROS), superoxide dismutase (SOD) and catalase (CAT) activities, cell membrane permeability of C. freundii and E. coli C600 were obviously increased under TCS stress. Scanning electron microscope showed that the cell membrane surface of the conjugative strains was wrinkled and pitted, even broken at 2.00 μg/L TCS, while lysed or even ruptured at 200.00 μg/L TCS. In addition, TCS up-regulated expression levels of oxidative stress genes ( kat E, hem F, bcp , hem A, kat G, ahp F, and ahp C) and cell membrane-related genes ( fim C, bam E and omp A) of donor and recipient bacteria. Gene Ontology (GO) enrichment demonstrated significant changes in categories relevant to pilus, porin activity, transmembrane transporter activity, transferase activity, hydrolase activity, material transport and metabolism. Taken together, a tet (X4)-resistant plasmid could horizontal transmission among different pathogens, while TCS can promote the propagation of the resistant plasmid.
研究领域:
微生物学
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分子生物学
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环境科学
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水产养殖
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公共卫生
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DOI
PubMed
高影响因子
Microorganisms
·
2026
·Vol. 14
·期 8
·1692
·
IF 4.7
Xiaokun Zhan,Lifeng Zhou,Hanyu Wang,Lihao Wang,Lizhi Tian,Yonglin Zhou,Kuan Gu,Houru Liu
The increased occurrence of tetracycline resistance (conferred by thetet(X3)/tet(X4) resistance genes) poses a major challenge to the clinical treatment of infections using tetracyclines, including tigecycline, which is the “last-resort” therapeutic agent. Thus, there is an urgent need to develop inhibitors targeting Tet(X3)/Tet(X4) to address the crisis of tetracycline resistance. This study revealed that quercetin is an inhibitor of Tet(X3)/Tet(X4), which, when combined with different tetracyclines, can exert synergistic growth-inhibitory effects against Tet(X3)/Tet(X4)-positive bacteria (fractional inhibitory concentration < 0.5). Quercetin + tigecycline significantly decreased the biofilm-forming ability of bacteria. Mechanistic investigations revealed that quercetin inhibits the catalytic activity of Tet(X4) against tetracycline antibiotics by binding to the catalytic active site. In theGalleria mellonellalarval infection model of Tet(X4)-positiveE. coliJ53p47EC or Tet(X4)-negativeE. coliJ53, tigecycline + quercetin enhanced the survival rate, decreased melanization, and suppressed bacterial load. Thus, the findings of this study will enable the development of novel Tet(X3)/Tet(X4)-targeted therapeutic strategies for clinical infections caused by drug-resistantEnterobacteriaceaeandAcinetobacter baumannii, especially Tet(X3)/Tet(X4)-positive pathogens.
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DOI
高影响因子
Animals
·
2025
·Vol. 15
·期 24
·3564
·
IF 2.7
Kaiwei Yang,Xi Wu,Bingcun Ma,Jianguo Cheng,Zengting Li,Yin Wang,Zexiao Yang,Xueping Yao,Yan Luo
Simple SummaryEscherichia coli(E. coli) is an opportunistic pathogen and an important reservoir of antibiotic resistance genes. Thetet(X4) gene mediates tigecycline resistance by encoding a flavin-dependent monooxygenase. However, the mechanism by which this gene influences bacterial antibiotic resistance through regulating the expression of other genes is complex and not yet fully understood. In this study,E. coli tet(X4) deletion and complemented strains were constructed to explore the effects of this gene on bacterial growth and antibiotic resistance. We measured the minimum inhibitory concentrations (MICs) of 24 antibiotics and the degradation capability for tetracycline/tigecycline in the wild type, deletion, and complemented strains, and conducted a 4-week starvation stress experiment (with/without subinhibitory concentrations of tigecycline) to analyze growth curves, survival rates, and changes in MICs. Transcriptome sequencing identified 531 differentially expressed genes, which are associated with ABC transporter activity, drug metabolism, and two-component systems. These findings provide reliable insights into the mechanism by which thetet(X4) gene affectsE. coliantibiotic resistance and offer a reference for the prevention and control of tigecycline-resistantE. coliinfections.Escherichia coli(E. coli) is a ubiquitous opportunistic pathogen in nature and serves as an important reservoir for antibiotic resistance genes. Thetet(X4) gene is a key determinant mediating tigecycline resistance. Although its core resistance mechanism, encoding a flavin-dependent monooxygenase, has been elucidated, the broader impact of thetet(X4) gene on the secondary regulatory networks ofE. coliremains not fully understood. In recent years, multiple studies have indicated that thetet(X4) gene participates in pathways contributing to resistance to other antibiotics by regulating the expression of various genes. In this study,E. coli tet(X4) gene deletion and complementation strains were constructed to investigate the mechanisms by which thetet(X4) gene influences the growth characteristics and antibiotic resistance ofE. coli. The minimum inhibitory concentrations (MICs) of 24 different antibiotics, as well as the degradation capacities of tetracycline and tigecycline, were determined for the wild-type, deletion, and complementation strains. In addition, a four-week starvation stress experiment was performed under both the presence and absence of sub-inhibitory concentrations of tigecycline, during which the bacterial growth curves, survival rates, and MIC variations were analyzed. Transcriptomic sequencing of the wild-type, deletion, and complementation strains identified 531 differentially expressed genes associated with ABC transporter activity, drug metabolism, and bacterial two-component systems. These findings provide reliable evidence for elucidating the mechanism by which thetet(X4) gene affectsE. coliresistance, offering valuable insights into the prevention and control of tigecycline-resistantE. coliinfections.
研究领域:
微生物学
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抗生素耐药
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分子遗传学
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转录组学
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传染病学
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产品关联
DOI
PubMed
高影响因子
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