Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of ant...Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.展开更多
Acinetobacter baumannii(A.baumannii)is well known for its virulence and persistence,particularly in intensive care units.Therefore,new strategies and candidates to treat A.baumannii infection are urgently needed consi...Acinetobacter baumannii(A.baumannii)is well known for its virulence and persistence,particularly in intensive care units.Therefore,new strategies and candidates to treat A.baumannii infection are urgently needed considering the emergence of drug-resistant bacteria.Polyphosphate kinase 1(PPK1)is required for bacterial survival as it is involved in maintaining antibiotic resistance or tolerance,pathogenesis,and adversity resistance.Multiple phenotypic assays related to virulence and persistence were performed in this study,and phloretin was shown to attenuate A.baumannii virulence and persistence by inhibiting PPK1 activity.Phloretin hampered mobility,interfered with biofilm formation and decreased resistance to ampicillin,heat,and hydrogen peroxide stress in A.baumannii.The therapeutic effect was also examined in a mouse pneumonia infection model.Molecular simulation and site-directed mutagenesis revealed that ARG-22,MET-622,ASN-57,and ARG-65 were the sites of phloretin action against PPK1.Phloretin treatment led to changes in metabolic pathways associated with A.baumannii virulence and persistence,including glycerophospholipid metabolism and fatty acid biosynthesis.Furthermore,phloretin alleviated pneumonic injury in a mouse pneumonia infection model in vivo,indicating that phloretin is a promising compound for preventing A.baumannii infection resistance by targeting PPK1.展开更多
Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disinteg...Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.展开更多
Withering is a critical process to form the unique aroma of high-quality white tea.To study the mechanism underlying aroma changes during the white withering,we herein conducted volatile metabolomics and transcriptomi...Withering is a critical process to form the unique aroma of high-quality white tea.To study the mechanism underlying aroma changes during the white withering,we herein conducted volatile metabolomics and transcriptomics of the young leaves from the'Fuding Dahaocha'tea cultivar.As the withering time extended,the content of major aroma components increased significantly,score of sensory evaluation and Owuor's flavor index(OFI)also increased.The aromatic substances that accumulated during white tea withering were mainly volatile terpenes and esters.Their change trends were largely consistent with the gene expression of theα-linolenic acid metabolic pathways,while the correlation between the trends in volatiles and the gene expression of the terpenoid biosynthesis pathways was more complex and induced by the jasmonic acid(JA)signaling pathway.Additionally,we also explored the regulation pattern of key genes in the signaling pathway by related transcription factors.Three coexpression networks strongly correlated to the variation of volatile component content during withering were identified by weighted gene coexpression network analysis(WGCNA).Our results provide a new perspective on the processing mechanism and quality improvement of white tea.展开更多
The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical e...The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat.Herein,versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance.2-methoxy-1,4-naphthoquinone(MNQ)exhib-ited the potent potentiation(4 to 32-fold)with tetracyclines,along with effective inhibition on biofilm formation.Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4)proteins through interaction with their active residues.Furthermore,exposure to MNQ significantly dissipate the proton motive force,leading to a cascade of membrane structural damage and metabolic homeostasis imbalance.Encouragingly,the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models,as evidenced by the reduced bacterial burden and mitigated pathological injury.Our find-ings propose a potential therapeutic option and a novel tetracyclines’adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4).展开更多
基金supported by the National Key Research and Development Program of China(2021YFD1801000)the Natural Science Foundation of China(32373066)+1 种基金the Natural Science Foundation of Jilin Province(20230101142JC)the Fundamental Research Funds for the Central Universities.
文摘Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.
基金supported by the National Natural Science Foundation of China(U23A20242 and U22A20523)the Fundamental Research Funds for the Central Universities under Grant 2023JCXK-01。
文摘Acinetobacter baumannii(A.baumannii)is well known for its virulence and persistence,particularly in intensive care units.Therefore,new strategies and candidates to treat A.baumannii infection are urgently needed considering the emergence of drug-resistant bacteria.Polyphosphate kinase 1(PPK1)is required for bacterial survival as it is involved in maintaining antibiotic resistance or tolerance,pathogenesis,and adversity resistance.Multiple phenotypic assays related to virulence and persistence were performed in this study,and phloretin was shown to attenuate A.baumannii virulence and persistence by inhibiting PPK1 activity.Phloretin hampered mobility,interfered with biofilm formation and decreased resistance to ampicillin,heat,and hydrogen peroxide stress in A.baumannii.The therapeutic effect was also examined in a mouse pneumonia infection model.Molecular simulation and site-directed mutagenesis revealed that ARG-22,MET-622,ASN-57,and ARG-65 were the sites of phloretin action against PPK1.Phloretin treatment led to changes in metabolic pathways associated with A.baumannii virulence and persistence,including glycerophospholipid metabolism and fatty acid biosynthesis.Furthermore,phloretin alleviated pneumonic injury in a mouse pneumonia infection model in vivo,indicating that phloretin is a promising compound for preventing A.baumannii infection resistance by targeting PPK1.
基金supported by the National Natural Science Foundation of China(U22A20523,32172912,and 32102722)the Interdisciplinary Integration and Innovation Project of Jilin University(JLUXKJC2021QZ04)。
文摘Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.
基金funded by the Fujian Agriculture and Forestry University Construction Project for Technological Innovation and Service System of Tea Industry Chain,grant number K1520005A and KH220095A.
文摘Withering is a critical process to form the unique aroma of high-quality white tea.To study the mechanism underlying aroma changes during the white withering,we herein conducted volatile metabolomics and transcriptomics of the young leaves from the'Fuding Dahaocha'tea cultivar.As the withering time extended,the content of major aroma components increased significantly,score of sensory evaluation and Owuor's flavor index(OFI)also increased.The aromatic substances that accumulated during white tea withering were mainly volatile terpenes and esters.Their change trends were largely consistent with the gene expression of theα-linolenic acid metabolic pathways,while the correlation between the trends in volatiles and the gene expression of the terpenoid biosynthesis pathways was more complex and induced by the jasmonic acid(JA)signaling pathway.Additionally,we also explored the regulation pattern of key genes in the signaling pathway by related transcription factors.Three coexpression networks strongly correlated to the variation of volatile component content during withering were identified by weighted gene coexpression network analysis(WGCNA).Our results provide a new perspective on the processing mechanism and quality improvement of white tea.
基金supported by the National Natural Science Foundation of China(grant No.U22A20523,32202856,32172912 and 32102723)the Postdoctoral Research Foundation of China(Certificate Number:2023 M731291)+1 种基金Interdisciplinary Integration and Innovation Project of JLU(JLUXKJC2021QZ04)the Graduate Innovation Fund of Jilin University(No.2022001).
文摘The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat.Herein,versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance.2-methoxy-1,4-naphthoquinone(MNQ)exhib-ited the potent potentiation(4 to 32-fold)with tetracyclines,along with effective inhibition on biofilm formation.Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4)proteins through interaction with their active residues.Furthermore,exposure to MNQ significantly dissipate the proton motive force,leading to a cascade of membrane structural damage and metabolic homeostasis imbalance.Encouragingly,the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models,as evidenced by the reduced bacterial burden and mitigated pathological injury.Our find-ings propose a potential therapeutic option and a novel tetracyclines’adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4).
