Journal of Global Antimicrobial Resistance
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2024
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IF 3.7
Xiaoqian Long,Feng Lin,Biao Tang,Fengcheng Miao,Zhiyu Li,Yao Shen,Hua Yang,Jiangang Ma
Objectives Acinetobacter indicus is an important pathogen of nosocomial infection. The purpose of this study was to analyze the resistance and transmission of A. indicus strain AIBD14 isolated from slaughterhouse environment. Methods A total of 96 environmental samples were collected from slaughterhouse. The antimicrobial susceptibility test was carried out by microbroth dilution method and E -test. Whole genome sequencing and bioinformatics analysis of the AIBD14 were performed, then S1-PFGE and southern blot verified the location of bla NDM-1 and tet (X6). Results The AIBD14 is resistant to meropenem but susceptibility to tigecycline, and coharboring bla NDM-1 and tet (X6). The bla NDM-1 is located on the pAIBD14-NDM-1 that cannot be transferred by conjugation. Specifically, bla NDM-1 is located on the transposon Tn 125 , and bla NDM-1 can be transferred to other species with the help of transposon. The genetic background of bla NDM-1 is "IS Aba125 - bla NDM-1 - ble MEL - dsbD - cutA - groES - groEL -insE-IS Aba125 ". pAIBD14-NDM-1 is classified into the GR31 plasmid based on the homology of the repB . Meanwhile, there are two XerC/D-like binding sites on the plasmid, which can mediate the transfer of resistance genes. The tet (X6) gene is located on the chromosome of AIBD14, its downstream is accompanied by the neglected macrolide resistance gene estT , and there is a single copy of the insertion element IS CR2 around tet (X6) as the genetic background "IS Aba4 -IS 3 -hp-hp- tet (X6)- estT - guaA -IS CR2 ". Conclusions This is the first report of the coexistence of tet (X6) and bla NDM-1 in the A. indicus , and it has the risk of horizontal transfer across multiple species. So strict monitoring the multiple-resistant bacteria in the industrial chain is necessary based on the "One Heath".
研究领域:
微生物学
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传染病学
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基因组学
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高影响因子
Antibiotics-Basel
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2022
·Vol. 11
·期 2
·162
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IF 5.222
Xia Xiao,Quanmin Huan,Yanhu Huang,Yuan Liu,Ruichao Li,Xilan Xu,Zhiqiang Wang
Tigecycline (TIG) is one of the last effective options against multidrug resistance bacteria. Recently, the RND (resistance–nodulation–division) efflux pump gene cluster,tmexCD1-toprJ1, and the tetracycline-efflux pumptet(A) mutation were reported to mediate high level resistance to TIG in clinically important pathogens, weakening the efficacy of TIG. In this study, we report the potent synergistic effect of the antidiabetic drug metformin in combination with TIG againsttet(A) mutant andtmexCD1-toprJ1positiveK. pneumoniae. The fractional inhibitory concentration index (FICI) of TIG and metformin were less than 0.05 for all the tested isolates. The time–kill curve assay showed that the combination of TIG and metformin exhibited much better antimicrobial effect than TIG alone. The synergistic effect was also confirmed in vivo using a well-studiedGalleria mellonellalarvae model. Mechanistic studies demonstrated that metformin disrupted the important component of proton motive force, the electric potential (Δψ) and the function of efflux pump, thereby increasing the intracellular concentration of TIG. This finding revealed that metformin might be a possible adjuvant of TIG for combating with superbugs carrying thetet(A) mutant andtmexCD1-toprJ1genes.Keywords:tigcycline;metformin;tmexCD1-toprJ1;tet(A);synergy
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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PubMed
高影响因子
Frontiers in Microbiology
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2024
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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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PubMed
高影响因子
BMC MICROBIOLOGY
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2025
·Vol. 25
·期 1
·805
·
IF 4.2
Zhou Qianyu,Xue Jinjing,Li Jun,Liu Zhiying,Zou Yinuo,Dai Rui,Gu Kuan,Zhou Yonglin
The advent and global spread of plasmid-carried resistance genes, including the tigecycline resistance gene tet (X3/X4) and the colistin resistance gene mcr-1 , present a substantial threat to public health that requires immediate resolution. This study successfully screened and identified commercial anti-parasitic drugs that efficiently inhibit Tet(X4) enzyme activity (IC 50 = 79.42 µg/mL), revealing that mefloquine exhibited a synergistic antibacterial effect with tetracyclines against tet (X3/X4)-positive bacteria (FIC < 0.5) and an additive effect with tetracyclines against tet (X3/X4)-negative bacteria (0.5 < FIC < 1, excluding minocycline). Molecular dynamics simulations and checkerboard minimum inhibitory concentration (MIC) tests on Tet(X4) mutants in amino acid residues demonstrated that mefloquine’s interaction with the active site of Tet(X4) reduces its activity. The energy contribution of the binding site residues involves PHE221, PHE316, GLY233, PRO315, PHE232, MET212, ALA222 and HIE231, which establish robust interactions with mefloquine (Δ Etotal of ≤ − 0.5 kcal/mol). Moreover, findings from metabonomics, bacterial membrane analysis, ROS detection, NAD + /NADH ratio determination, and intracellular ATP determination indicated that mefloquine may significantly influence bacterial energy metabolism ( P < 0.05). Furthermore, in the mouse infection model of E. coli 47EC, the combination of methacycline and mefloquine, demonstrated significant therapeutic advantages, as evidenced by an increased survival rate (from 20.00% to 80.00%), decreased sepsis score, and decreased bacterial load. Our work is the first to reveal that the commercial medicine mefloquine can prolong the efficacy of tetracycline and treat infections caused by drug-resistant Enterobacteriaceae in clinical environments. Graphical
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VETERINARY MICROBIOLOGY
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2023
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IF 3.3
Yumeng Cheng,Yakun Li,Meng Yang,Yang He,Xinru Shi,Zhidan Zhang,Yesheng Zhong,Yuan Zhang,Hongbin Si
Antibiotic-resistant bacteria are emerging all the time, but the continued emergence of novel resistance genes and genetic structures is even more alarming. Tigecycline is currently the important last barrier in the treatment of multidrug-resistant (MDR) infections. tet (X), a resistance gene to tigecycline, is the most prevalent and constantly emerging novel variants. In this research, we characterized two MDR Acinetobacter indicus strains to tigecycline that were identified and analyzed by antimicrobial susceptibility testing, conjugation transfer, whole genome sequencing (WGS) and bioinformatics analysis, and gene function analysis. The results showed that three tet (X) variants were carried in BDT201, including tet (X6) on the chromosome, tet (X3) on the plasmid pBDT201–2, and a novel tet (X5) variant adjacent to the IS Aba1 elements on the plasmid pBDT201–3. The novel Tet(X5) variant showed 98.7% amino acid identity with Tet(X5) and was named Tet(X5.4). By expressing tet (X5.4) gene, the tigecycline minimum inhibitory concentration (MIC) values for Escherichia coli JM109 increased 32- fold (from 0.13 to 4 mg/L). BDT2076 contained tigecycline and carbapenems resistance genes, such as tet (X3), bla OXA-58 , bla NDM-3 , and bla CARB-2 . The continuous emergence of MDR bacteria and resistance genes is a global environmental health issue that can not be ignored and therefore needs to pay more urgent attention to it.
研究领域:
微生物学
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分子生物学
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抗生素研究
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环境健康
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DOI
高影响因子
Cell Communication and Signaling
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2024
·Vol. 22
·期 1
·1-22
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IF 8.2
Wu Xiao,Tang Ying,Lu Xinxing,Liu Yigao,Liu Xu,Sun Qin,Wang Lu,Huang Wei,Liu Airan,Liu Ling,Chao Jie,Zhang Xiwen,Qiu Haibo
Background Acute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms. Methods EVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms. Results Compared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs. Conclusions This study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.
研究领域:
肺科学
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干细胞生物学
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分子生物学
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免疫学
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细胞生物学
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DOI
PubMed
高影响因子
Microorganisms
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2026
·Vol. 14
·期 8
·1692
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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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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2019
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IF 4.527
Sicheng Shao,Yongyou Hu,Jianhua Cheng,Yuancai Chen
In this study, the characteristics of biodegradation of oxytetracycline (OTC) by strain Ochrobactrum sp. KSS10 were studied under various environmental conditions, including initial OTC concentrations, variable temperature, initial pH, and diverse carbon sources. The capability of this bacterial strain for performing simultaneous OTC degradation and nitrate reduction was also explored under aerobic conditions . An OTC degradation ratio of 63.33% and a nitrate removal ratio of 98.64% were obtained within 96 h. In addition, removal of OTC and ammonia from synthetic aquaculture wastewater by a Moving Bed Biofilm Reactor (MBBR) and changes in the resistant genes of microbial communities were also investigated. The results demonstrated that the strain KSS10 was the dominant contributor in OTC and ammonia removal in the MBBR chamber. It removed almost all ammonia and approximately 76.42% of OTC. The abundances of genes tet L, tet X and intI 1 were reduced by the MBBR, but the abundance of tet G and tet M were increased due to horizontal and vertical gene transfers. Such a result can potentially be used by the strain KSS10 for removing antibiotics and nitrogen from aquaculture wastewater during pre-treatment.
研究领域:
环境工程
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微生物学
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废水处理
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水产养殖
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PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2024
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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
Cell Reports
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2024
·
IF 7.5
Weigang Wang,Na Yang,Liangliang Wang,Yuanxiang Zhu,Xiao Chu,Weijie Xu,Yawei Li,Yihai Xu,Lina Gao,Beibei Zhang,Guoqiang Zhang,Qinmiao Sun,Weihong Wang,Qiang Wang,Wenxin Zhang,Dahua Chen
Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.
研究领域:
发育生物学
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分子遗传学
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颅面生物学
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PubMed
高影响因子
AVIAN DISEASES
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2025
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IF 1.3
Du Xiaowen,Zeng Mengting,Yang Wenzhuo,Jiang Yuting,Huang Guangyu,Ding Shiping,Jiang Danli,Yuan Zhaoxia
For decades, infectious bronchitis (IB), caused by the infectious bronchitis virus (IBV), has posed a significant threat to poultry health and is mainly controlled by vaccines. However, the currently available commercial vaccines do not provide adequate protection against new IBV strains that emerge due to ongoing evolution. Therefore, new antiviral strategies need to be explored. Cepharanthine (CEP), tetrandrine (TET), and berbamine hydrochloride (BBM) are natural plant-derived bis-benzylisoquinoline alkaloids (BBAs) with proven antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), porcine epidemic diarrhea virus (PEDV), and other viruses. Despite this, their potential antiviral activities against IBV remain unknown. As a proof-of-concept study, we aimed to investigate the inhibitory effects of CEP, TET, and BBM on the laboratory-adapted IBV Beaudette strain in Vero cells and of CEP in chicken embryos. Our research demonstrated that CEP, TET, and BBM effectively suppressed IBV infection in Vero cells, with CEP showing a particularly high selective index of 309.6. These compounds dose-dependently decreased IBV RNA levels and N protein expression and lowered intracellular and extracellular viral titers. Notably, CEP also exhibited antiviral activity against IBV infection in chicken embryos, resulting in reduced mortality and fewer lesions. While these findings highlight the potential of CEP, TET, and BBM as candidates for further development, further studies are required to evaluate their efficacy against field-prevalent IBV strains (e.g., Massachusetts, QX-like) and clarify the specific antiviral mechanisms.
研究领域:
病毒学
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药物开发
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兽医学
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PubMed
高影响因子
ANALYTICA CHIMICA ACTA
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2023
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IF 6.2
Jie Xiang,Junyi Zhang,Lei Liao,Bingying Jiang,Ruo Yuan,Yun Xiang
The sensitive detection of ten-eleven translocation (TET) dioxygenase is of significance for understanding the demethylation mechanism of 5-methylocytosine (5mC), which is responsible for a wide range of biological functions that can affect gene expression in eukaryotic species. Here, a non-label and sensitive fluorescence biosensing method for TET assay using TET1 as the model target molecule is established on the basis of target-triggered Mg 2+ -dependent DNAzyme and catalytic hairpin assembly (CHA)-mediated multiple signal amplification cascades. 5mC sites in the hairpin DNA probe are first oxidized by TET1 into 5-carboxycytosine, which are further reduced by pyridine borane into dihydrouracil , followed by its recognition and cleavage by the USER enzyme to liberate active DNAzyme and G-quadruplex sequences from the probe. The DNAzyme further cyclically cleaves the substrate hairpins to trigger subsequent CHA reaction and DNAzyme cleavage cycles for yielding many G-quadruplex strands. Thioflavin T dye then intercalates into G-quadruplexes to cause a magnificent increase of fluorescence for high sensitivity assay of TET1 with 47 fM detection limit. And, application of this method for TET1 monitoring in diluted serum has also been confirmed.
研究领域:
生物化学
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分子生物学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）