Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens.Adjunctive str...Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens.Adjunctive strategies targeting bacterial virulence factors have been con-sidered to aid the host immune response in fighting the infection.Previous studies suggest that the US FDA–approved anti-inflammatory drug diflunisal inhibits Staphylococcus aureus(SA)α-toxin expression by its interaction with the response regulator AgrA.We investigated the broader antivirulence properties of diflunisal against pathogenic strains of SA and established proof-of-concept for its efficacy in blocking SA virulence.Our studies reveal that diflunisal inhibitsα-toxin production,sensitizes SA to cationic antibiotics and human antimi-crobial peptides,inhibits the production of the golden pigment staphyloxanthin,and reduces biofilm formation.Molecular docking simula-tions revealed potential interactions between diflunisal and AgrA binding sites.In addition,sequence alignment of the SA AgrA response regulator demonstrated similarities to other response regulators involved in controlling virulence factor expression.Appreciation of the antivirulence properties of diflunisal supports a therapeutic strategy distinct from structurally similar compounds,such as salicylic acid.The repurposing of diflunisal may mitigate disease severity and provide a unique adjunctive tool in the treatment of SA infection.展开更多
Antibiotic resistance is an unrelenting global health crisis.The overuse of antibiotics has led to the emergence of multidrug-resistant bacteria,making infections increasingly difficult to treat.To combat this,novel t...Antibiotic resistance is an unrelenting global health crisis.The overuse of antibiotics has led to the emergence of multidrug-resistant bacteria,making infections increasingly difficult to treat.To combat this,novel therapeutic approaches are urgently needed.Current strategies include antivirulence therapy,passive immunization,antimicrobial peptides,vaccines,phage therapy,and botanical and liposomal nanoparticles.These methods aim to reduce the pressure on antibiotics to mitigate the development of resistance.Future directions involve exploring combination therapies that combine antibiotics with biologics and nonantibiotic adjuvants.Intelligent delivery strategies and antimicrobial stewardship are also crucial for effective infection control.By integrating these approaches,we can combat antibiotic resistance and protect the natural microbiome.This article reviews these multifaceted strategies to highlight the ongoing battle against antibiotic resistance and how it can be better managed to ultimately preserve the effectiveness of antibiotics for future generations.展开更多
Listeria monocytogenes is a human and veterinary pathogen,one of the most common agents of foodborne infections worldwide.It can cause severe complications such as meningitis or miscarriage.Antivirulence therapies,whi...Listeria monocytogenes is a human and veterinary pathogen,one of the most common agents of foodborne infections worldwide.It can cause severe complications such as meningitis or miscarriage.Antivirulence therapies,which target virulence factors such as pore-forming toxins,offer an alternative approach to combating infections.In this study,cholesterol-containing liposomal nanotraps effec-tively neutralized L.monocytogenes exotoxins,particularly listeriolysin O,thereby protecting mammalian cells.Notably,toxin neutraliza-tion was observed under both neutral and acidic conditions,where listeriolysin O activity is optimized to facilitate bacterial escape from the phagosome.Liposomal nanotraps were phagocytosed by macrophages and colocalized with intracellular Listeria,increasing the clearance rate of intracellular bacteria.These findings expand the potential use of broad-spectrum liposomal nanotrap therapy,which could be employed alongside current standard of care treatments to assist the immune system in controlling virulent pathogens.展开更多
Given their dangerous effects on the nervous system,neurotoxins represent a significant threat to public health.Various therapeutic approaches,including chelating agents,receptor decoys,and toxin-neutralizing antibodi...Given their dangerous effects on the nervous system,neurotoxins represent a significant threat to public health.Various therapeutic approaches,including chelating agents,receptor decoys,and toxin-neutralizing antibodies,have been explored.While prophylactic vaccines are desirable,it is oftentimes difficult to effectively balance their safety and efficacy given the highly dangerous nature of neurotoxins.To address this,we report here on a nanovaccine against neurotoxins that leverages the detoxifying properties of cell membrane-coated nanoparticles.A genetically modified cell line with constitutive overexpression of theα7 nicotinic acetylcholine receptor is developed as a membrane source to generate biomimetic nanoparticles that can effectively and irreversibly bind toα-bungarotoxin,a model neurotoxin.This abrogates the biological activity of the toxin,enabling the resulting nanotoxoid to be safely delivered into the body and processed by the immune system.When co-administered with an immunological adjuvant,a strong humoral response againstα-bungarotoxin is generated that protects vaccinated mice against a lethal dose of the toxin.Overall,this work highlights the potential of using genetic modification strategies to develop nanotoxoid formulations against various biological threats.展开更多
基金supported by the US National Institutes of Health grants(R01-AI145325)This work was also supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences,T32 GM007752The funder had no role in the study design,data collection or analysis,decision to publish,or preparation of the manuscript.MSMS acknowledges his PDE scholarship by CNPq(200069/2024-1).
文摘Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens.Adjunctive strategies targeting bacterial virulence factors have been con-sidered to aid the host immune response in fighting the infection.Previous studies suggest that the US FDA–approved anti-inflammatory drug diflunisal inhibits Staphylococcus aureus(SA)α-toxin expression by its interaction with the response regulator AgrA.We investigated the broader antivirulence properties of diflunisal against pathogenic strains of SA and established proof-of-concept for its efficacy in blocking SA virulence.Our studies reveal that diflunisal inhibitsα-toxin production,sensitizes SA to cationic antibiotics and human antimi-crobial peptides,inhibits the production of the golden pigment staphyloxanthin,and reduces biofilm formation.Molecular docking simula-tions revealed potential interactions between diflunisal and AgrA binding sites.In addition,sequence alignment of the SA AgrA response regulator demonstrated similarities to other response regulators involved in controlling virulence factor expression.Appreciation of the antivirulence properties of diflunisal supports a therapeutic strategy distinct from structurally similar compounds,such as salicylic acid.The repurposing of diflunisal may mitigate disease severity and provide a unique adjunctive tool in the treatment of SA infection.
文摘Antibiotic resistance is an unrelenting global health crisis.The overuse of antibiotics has led to the emergence of multidrug-resistant bacteria,making infections increasingly difficult to treat.To combat this,novel therapeutic approaches are urgently needed.Current strategies include antivirulence therapy,passive immunization,antimicrobial peptides,vaccines,phage therapy,and botanical and liposomal nanoparticles.These methods aim to reduce the pressure on antibiotics to mitigate the development of resistance.Future directions involve exploring combination therapies that combine antibiotics with biologics and nonantibiotic adjuvants.Intelligent delivery strategies and antimicrobial stewardship are also crucial for effective infection control.By integrating these approaches,we can combat antibiotic resistance and protect the natural microbiome.This article reviews these multifaceted strategies to highlight the ongoing battle against antibiotic resistance and how it can be better managed to ultimately preserve the effectiveness of antibiotics for future generations.
基金supported by the Multidisciplinary Center for Infectious Diseases(MCID)(SA_02 to EB)the Swiss National Science Foundation(P500PB_222029 to HB).
文摘Listeria monocytogenes is a human and veterinary pathogen,one of the most common agents of foodborne infections worldwide.It can cause severe complications such as meningitis or miscarriage.Antivirulence therapies,which target virulence factors such as pore-forming toxins,offer an alternative approach to combating infections.In this study,cholesterol-containing liposomal nanotraps effec-tively neutralized L.monocytogenes exotoxins,particularly listeriolysin O,thereby protecting mammalian cells.Notably,toxin neutraliza-tion was observed under both neutral and acidic conditions,where listeriolysin O activity is optimized to facilitate bacterial escape from the phagosome.Liposomal nanotraps were phagocytosed by macrophages and colocalized with intracellular Listeria,increasing the clearance rate of intracellular bacteria.These findings expand the potential use of broad-spectrum liposomal nanotrap therapy,which could be employed alongside current standard of care treatments to assist the immune system in controlling virulent pathogens.
基金supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense under award number HDTRA1-21-1-0010the National Institutes of Health under Award Numbers R21AI159492 and R21AI175904.
文摘Given their dangerous effects on the nervous system,neurotoxins represent a significant threat to public health.Various therapeutic approaches,including chelating agents,receptor decoys,and toxin-neutralizing antibodies,have been explored.While prophylactic vaccines are desirable,it is oftentimes difficult to effectively balance their safety and efficacy given the highly dangerous nature of neurotoxins.To address this,we report here on a nanovaccine against neurotoxins that leverages the detoxifying properties of cell membrane-coated nanoparticles.A genetically modified cell line with constitutive overexpression of theα7 nicotinic acetylcholine receptor is developed as a membrane source to generate biomimetic nanoparticles that can effectively and irreversibly bind toα-bungarotoxin,a model neurotoxin.This abrogates the biological activity of the toxin,enabling the resulting nanotoxoid to be safely delivered into the body and processed by the immune system.When co-administered with an immunological adjuvant,a strong humoral response againstα-bungarotoxin is generated that protects vaccinated mice against a lethal dose of the toxin.Overall,this work highlights the potential of using genetic modification strategies to develop nanotoxoid formulations against various biological threats.
