Yuxuan Wu, Yufan Pang, Han Yang, Li Zhu, Tonghui Ma, Xiuli Chen
{"title":"重新设计的抗多发性硬化症药物 Fty720 通过多种途径靶向耐碳青霉烯类鲍曼不动杆菌","authors":"Yuxuan Wu, Yufan Pang, Han Yang, Li Zhu, Tonghui Ma, Xiuli Chen","doi":"10.1007/s00284-024-03986-1","DOIUrl":null,"url":null,"abstract":"<p><p>Bacterial antimicrobial resistance (AMR), particularly multidrug resistance (MDR) in gram-negative bacterial strains, has emerged as a formidable challenge of substantial consequence, necessitating an urgent pursuit of a sustainable and efficacious strategic response. Repurposing nonantibiotic drugs as potential antibiotics or antibiotic adjuvants is a valuable approach to targeting MDR bacteria. A total of 1,750 FDA-approved drugs (APExBIO, USA) were screened to test their antimicrobial activities against MDR bacteria using the broth microdilution method according to the standard of the Clinical and Laboratory Standards Institute (CLSI). Microscale thermophoresis (MST) analysis was performed to detect the Fty720-LPS interactions. Fty720-indcued lipid changes were measured by untargeted lipidomic analysis. Isothermal titration calorimetry (ITC) analysis was used to determine the Fty720-lipid binding affinities. DNA degradation was assessed via agarose gel electrophoresis with ethidium bromide (EB) staining and visualized using a gel imaging system. Galleria mellonella larvae infection model and Mouse peritonitis infection models were used to evaluated the antibacterial ability of Fty720 in vivo. In this study, we identified Fty720, a pharmaceutical agent for treating multiple sclerosis, as a potent inhibitor of carbapenem-resistant Acinetobacter baumannii (CRAB). We demonstrated that Fty720 exerts antibacterial effects through multiple strategies, including disruption of the structural integrity of the membranes by interacting with LPS and glycerophospholipids, as well as degradation of bacterial DNA. Furthermore, through judicious structural modification, the pivotal role of the positively charged moiety (NH2) in Fty720's antibacterial activity was substantiated. Intriguingly, the translation of Fty720's antibacterial efficacy was demonstrated in vivo, substantiating its pronounced influence on elevating survival rates among models afflicted with MDR gram-negative bacterial infections. Fty720 targets CRAB via multiple pathways, including disruption of outer and inner membrane integrity and DNA degradation. This investigation unveils the multifaceted antibacterial mechanisms of Fty720 while concurrently delineating a prospective therapeutic avenue to counteract MDR gram-negative bacterial strains.</p>","PeriodicalId":11360,"journal":{"name":"Current Microbiology","volume":"82 1","pages":"17"},"PeriodicalIF":2.3000,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Repurposed Anti-Multiple Sclerosis Drug Fty720 Targets Carbapenem-Resistant Acinetobacter baumannii via Multiple Pathways.\",\"authors\":\"Yuxuan Wu, Yufan Pang, Han Yang, Li Zhu, Tonghui Ma, Xiuli Chen\",\"doi\":\"10.1007/s00284-024-03986-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Bacterial antimicrobial resistance (AMR), particularly multidrug resistance (MDR) in gram-negative bacterial strains, has emerged as a formidable challenge of substantial consequence, necessitating an urgent pursuit of a sustainable and efficacious strategic response. Repurposing nonantibiotic drugs as potential antibiotics or antibiotic adjuvants is a valuable approach to targeting MDR bacteria. A total of 1,750 FDA-approved drugs (APExBIO, USA) were screened to test their antimicrobial activities against MDR bacteria using the broth microdilution method according to the standard of the Clinical and Laboratory Standards Institute (CLSI). Microscale thermophoresis (MST) analysis was performed to detect the Fty720-LPS interactions. Fty720-indcued lipid changes were measured by untargeted lipidomic analysis. Isothermal titration calorimetry (ITC) analysis was used to determine the Fty720-lipid binding affinities. DNA degradation was assessed via agarose gel electrophoresis with ethidium bromide (EB) staining and visualized using a gel imaging system. Galleria mellonella larvae infection model and Mouse peritonitis infection models were used to evaluated the antibacterial ability of Fty720 in vivo. In this study, we identified Fty720, a pharmaceutical agent for treating multiple sclerosis, as a potent inhibitor of carbapenem-resistant Acinetobacter baumannii (CRAB). We demonstrated that Fty720 exerts antibacterial effects through multiple strategies, including disruption of the structural integrity of the membranes by interacting with LPS and glycerophospholipids, as well as degradation of bacterial DNA. Furthermore, through judicious structural modification, the pivotal role of the positively charged moiety (NH2) in Fty720's antibacterial activity was substantiated. Intriguingly, the translation of Fty720's antibacterial efficacy was demonstrated in vivo, substantiating its pronounced influence on elevating survival rates among models afflicted with MDR gram-negative bacterial infections. Fty720 targets CRAB via multiple pathways, including disruption of outer and inner membrane integrity and DNA degradation. This investigation unveils the multifaceted antibacterial mechanisms of Fty720 while concurrently delineating a prospective therapeutic avenue to counteract MDR gram-negative bacterial strains.</p>\",\"PeriodicalId\":11360,\"journal\":{\"name\":\"Current Microbiology\",\"volume\":\"82 1\",\"pages\":\"17\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-11-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current Microbiology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s00284-024-03986-1\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Microbiology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00284-024-03986-1","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
Repurposed Anti-Multiple Sclerosis Drug Fty720 Targets Carbapenem-Resistant Acinetobacter baumannii via Multiple Pathways.
Bacterial antimicrobial resistance (AMR), particularly multidrug resistance (MDR) in gram-negative bacterial strains, has emerged as a formidable challenge of substantial consequence, necessitating an urgent pursuit of a sustainable and efficacious strategic response. Repurposing nonantibiotic drugs as potential antibiotics or antibiotic adjuvants is a valuable approach to targeting MDR bacteria. A total of 1,750 FDA-approved drugs (APExBIO, USA) were screened to test their antimicrobial activities against MDR bacteria using the broth microdilution method according to the standard of the Clinical and Laboratory Standards Institute (CLSI). Microscale thermophoresis (MST) analysis was performed to detect the Fty720-LPS interactions. Fty720-indcued lipid changes were measured by untargeted lipidomic analysis. Isothermal titration calorimetry (ITC) analysis was used to determine the Fty720-lipid binding affinities. DNA degradation was assessed via agarose gel electrophoresis with ethidium bromide (EB) staining and visualized using a gel imaging system. Galleria mellonella larvae infection model and Mouse peritonitis infection models were used to evaluated the antibacterial ability of Fty720 in vivo. In this study, we identified Fty720, a pharmaceutical agent for treating multiple sclerosis, as a potent inhibitor of carbapenem-resistant Acinetobacter baumannii (CRAB). We demonstrated that Fty720 exerts antibacterial effects through multiple strategies, including disruption of the structural integrity of the membranes by interacting with LPS and glycerophospholipids, as well as degradation of bacterial DNA. Furthermore, through judicious structural modification, the pivotal role of the positively charged moiety (NH2) in Fty720's antibacterial activity was substantiated. Intriguingly, the translation of Fty720's antibacterial efficacy was demonstrated in vivo, substantiating its pronounced influence on elevating survival rates among models afflicted with MDR gram-negative bacterial infections. Fty720 targets CRAB via multiple pathways, including disruption of outer and inner membrane integrity and DNA degradation. This investigation unveils the multifaceted antibacterial mechanisms of Fty720 while concurrently delineating a prospective therapeutic avenue to counteract MDR gram-negative bacterial strains.
期刊介绍:
Current Microbiology is a well-established journal that publishes articles in all aspects of microbial cells and the interactions between the microorganisms, their hosts and the environment.
Current Microbiology publishes original research articles, short communications, reviews and letters to the editor, spanning the following areas:
physiology, biochemistry, genetics, genomics, biotechnology, ecology, evolution, morphology, taxonomy, diagnostic methods, medical and clinical microbiology and immunology as applied to microorganisms.