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
Intracellular bacteria can multiply inside host cells and manipulate their biology,and the efficacy of traditional antibiotic drug therapy for intracellular bacteria is limited by inadequate drug accumulation.Fighting...Intracellular bacteria can multiply inside host cells and manipulate their biology,and the efficacy of traditional antibiotic drug therapy for intracellular bacteria is limited by inadequate drug accumulation.Fighting against these stealthy bacteria has been a longstanding challenge.Here,a system of stimuli-responsive lactoferrin(Lf)nanoparticles is prepared using protein self-assembly technology to deliver broad-spectrum antibiotic rifampicin(Rif)(Rif@Lf NPs)for enhanced infection therapy through targeted elimination of intracellular bacteria.Compared to Rif@BSA NPs,the Rif@Lf NPs can specifically target macrophages infected by bacteria,thus increasing the accumulation of Rif within macrophages.Subsequently,Rif@Lf NPs with positive surface charge further displayed targeted adherence to the bacteria within macrophages and released Rif rapidly in a redoxresponsive manner.Combined with the antibacterial activities of Lf and Rif,the Rif@Lf NPs showed broad-spectrum antibiotic abilities to intracellular bacteria and biofilms.As a result,the Rif@Lf NPs with high safety exhibited excellent therapeutic efficacy in the disease models of subcutaneous infection,sepsis,and bacterial keratitis.Taken together,the antibiotic-loaded Lf nanoparticles present a promising platform to combat pathogen infections through targeted elimination of intracellular bacteria.展开更多
Lactic acid bacteria possess several interesting properties of great economic importance. Improvement and stabilization of these industrially important features are an active research area at the present time. The obj...Lactic acid bacteria possess several interesting properties of great economic importance. Improvement and stabilization of these industrially important features are an active research area at the present time. The objectives of this work are to study the effect of freezing and freeze-drying on the survival rate, autolytic activity and intracellular enzymatic activity of the main species of lactic acid bacteria used in the dairy industry. The article focused on several characteristics that were not well covered in the past. The obtained results revealed that both preservation methods have a significant effect on viability, autolytic activity and intracellular enzymatic activity. After six months of storage we found that frozen cultures exhibited higher survival rate, higher rate of intracellular enzymatic activity and lower rate of autolysis. The impact of conservation treatments was only strain specific in the case of survival rate. The results obtained lead to the selection of the best preservation method for the selected cultures based on survival rate, autolytic activity and intracellular enzymatic activity.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support from the National Natural Science Foundation of China(Nos.22275081,82372117)Guangzhou Science and Technology Bureau(202206010068)China Postdoctoral Science Foundation(2022M711532 and 2022T150302).
文摘Intracellular bacteria can multiply inside host cells and manipulate their biology,and the efficacy of traditional antibiotic drug therapy for intracellular bacteria is limited by inadequate drug accumulation.Fighting against these stealthy bacteria has been a longstanding challenge.Here,a system of stimuli-responsive lactoferrin(Lf)nanoparticles is prepared using protein self-assembly technology to deliver broad-spectrum antibiotic rifampicin(Rif)(Rif@Lf NPs)for enhanced infection therapy through targeted elimination of intracellular bacteria.Compared to Rif@BSA NPs,the Rif@Lf NPs can specifically target macrophages infected by bacteria,thus increasing the accumulation of Rif within macrophages.Subsequently,Rif@Lf NPs with positive surface charge further displayed targeted adherence to the bacteria within macrophages and released Rif rapidly in a redoxresponsive manner.Combined with the antibacterial activities of Lf and Rif,the Rif@Lf NPs showed broad-spectrum antibiotic abilities to intracellular bacteria and biofilms.As a result,the Rif@Lf NPs with high safety exhibited excellent therapeutic efficacy in the disease models of subcutaneous infection,sepsis,and bacterial keratitis.Taken together,the antibiotic-loaded Lf nanoparticles present a promising platform to combat pathogen infections through targeted elimination of intracellular bacteria.
文摘Lactic acid bacteria possess several interesting properties of great economic importance. Improvement and stabilization of these industrially important features are an active research area at the present time. The objectives of this work are to study the effect of freezing and freeze-drying on the survival rate, autolytic activity and intracellular enzymatic activity of the main species of lactic acid bacteria used in the dairy industry. The article focused on several characteristics that were not well covered in the past. The obtained results revealed that both preservation methods have a significant effect on viability, autolytic activity and intracellular enzymatic activity. After six months of storage we found that frozen cultures exhibited higher survival rate, higher rate of intracellular enzymatic activity and lower rate of autolysis. The impact of conservation treatments was only strain specific in the case of survival rate. The results obtained lead to the selection of the best preservation method for the selected cultures based on survival rate, autolytic activity and intracellular enzymatic activity.
