ACS Infectious Diseases最新文献_第9页

Group B Streptococcal Membrane Vesicles Induce Proinflammatory Cytokine Production and Are Sensed in an NLRP3 Inflammasome-Dependent Mechanism in a Human Macrophage-like Cell Line

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-01-06 DOI: 10.1021/acsinfecdis.4c0064110.1021/acsinfecdis.4c00641

Cole R. McCutcheon, Jennifer A. Gaddy, David M. Aronoff, Shannon D. Manning* and Margaret G. Petroff*,

{"title":"Group B Streptococcal Membrane Vesicles Induce Proinflammatory Cytokine Production and Are Sensed in an NLRP3 Inflammasome-Dependent Mechanism in a Human Macrophage-like Cell Line","authors":"Cole R. McCutcheon, Jennifer A. Gaddy, David M. Aronoff, Shannon D. Manning* and Margaret G. Petroff*, ","doi":"10.1021/acsinfecdis.4c0064110.1021/acsinfecdis.4c00641","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00641https://doi.org/10.1021/acsinfecdis.4c00641","url":null,"abstract":"Group B Streptococcus (GBS) is a major cause of fetal and neonatal mortality worldwide. Many of the adverse effects of invasive GBS are associated with inflammation; therefore, understanding bacterial factors that promote inflammation is of critical importance. Membrane vesicles (MVs), which are produced by many bacteria, may modulate host inflammatory responses. While it is known that mice injected intra-amniotically with GBS MVs exhibit large-scale leukocyte infiltration, preterm birth, and subsequent fetal death, the immune effectors driving this response remain unclear. Here, we hypothesized that THP-1 macrophage-like cells respond to GBS-derived MVs by producing proinflammatory cytokines and are recognized through one or more pattern recognition receptors. We show that THP-1s produce high levels of neutrophil- and monocyte-specific chemokines in response to MVs derived from different clinical isolates of GBS. Using antibody microarrays and multiplex Luminex assays, we found that GBS MVs elicit significantly (p < 0.05) higher levels of CCL1, CCL2, CCL20, CXCL1, CXCL10, and IL-1β relative to untreated THP-1s. Using chemical inhibitors in combination with caspase-1 activity assays and Luminex assays, we further demonstrate that GBS MVs upregulated IL-1β production in a caspase-1 and NLRP3-dependent manner, ultimately identifying NLRP3 as a sensor of GBS MVs. These data indicate that MVs contain one or more pathogen-associated molecular patterns that can be sensed by the immune system and show that the NLRP3 inflammasome is a novel sensor of GBS MVs. Our data additionally indicate that MVs may serve as immune effectors that can be targeted for immunotherapeutics.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"453–462 453–462"},"PeriodicalIF":4.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-01-03 DOI: 10.1021/acsinfecdis.4c0065710.1021/acsinfecdis.4c00657

Juan Xiong, Hui Lu* and Yuanying Jiang*,

{"title":"Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches","authors":"Juan Xiong, Hui Lu* and Yuanying Jiang*, ","doi":"10.1021/acsinfecdis.4c0065710.1021/acsinfecdis.4c00657","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00657https://doi.org/10.1021/acsinfecdis.4c00657","url":null,"abstract":"The emergence of azole resistance and tolerance in pathogenic fungi has emerged as a significant public health concern, emphasizing the urgency for innovative strategies to bolster the efficacy of azole-based treatments. Drug repurposing stands as a promising and practical avenue for advancing antifungal therapy, with the potential for swift clinical translation. This review offers a comprehensive overview of azole synergistic agents uncovered through drug repurposing strategies, alongside an in-depth exploration of the mechanisms by which these agents augment azole potency. Drawing from these mechanisms, we delineate strategies aimed at enhancing azole effectiveness, such as inhibiting efflux pumps to elevate azole concentrations within fungal cells, intensifying ergosterol synthesis inhibition, mitigating fungal cell resistance to azoles, and disrupting biological processes extending beyond ergosterol synthesis. This review is beneficial for the development of these potentiators, as it meticulously examines instances and provides nuanced discussions on the mechanisms underlying the progression of azole potentiators through drug repurposing strategies.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"305–322 305–322"},"PeriodicalIF":4.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic Insights into the Divergent Membrane Activities of a Viroporin from Chikungunya Virus and Its Transframe Variant

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-01-02 DOI: 10.1021/acsinfecdis.4c0056210.1021/acsinfecdis.4c00562

Kirti Suhag, Subhomoi Borkotoky, Shumaila Iqbal Siddiqui, Jitender Kumar, Chandra Shekhar Kumar, Pushkar Tatiya, Subhendu Ghosh and Manidipa Banerjee*,

{"title":"Mechanistic Insights into the Divergent Membrane Activities of a Viroporin from Chikungunya Virus and Its Transframe Variant","authors":"Kirti Suhag, Subhomoi Borkotoky, Shumaila Iqbal Siddiqui, Jitender Kumar, Chandra Shekhar Kumar, Pushkar Tatiya, Subhendu Ghosh and Manidipa Banerjee*, ","doi":"10.1021/acsinfecdis.4c0056210.1021/acsinfecdis.4c00562","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00562https://doi.org/10.1021/acsinfecdis.4c00562","url":null,"abstract":"Alphaviruses, a genus of vector-borne viruses in the Togaviridae family, encode a small ion-channel-forming protein, 6K, and its transframe variant (TF) during infections. Although 6K/TF have vital roles in glycoprotein transport, virus assembly, and budding, there is no mechanistic explanation for these functions. We investigated the distinct biochemical functionalities of 6K and TF from the mosquito-borne alphavirus, Chikungunya Virus. We show that like 6K, TF is also capable of forming ion channels in bilayer membranes. The assemblies formed by 6K in membranes are structurally more complex and potentially more ion-restrictive than those formed by TF. Both 6K and TF show strong affinity toward the ER membranes, indicating that the localization of these components at the plasma membrane, as previously reported, is either linked to post-translational modification or mediated through interaction with binding partners. These structural and functional insights may elucidate the distinct roles of 6K and TF in the alphavirus life cycle.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"430–441 430–441"},"PeriodicalIF":4.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetically Recoding Respiratory Syncytial Virus to Visualize Nucleoprotein Dynamics and Virion Assembly

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-01-01 DOI: 10.1021/acsinfecdis.4c0032110.1021/acsinfecdis.4c00321

Margaret Dianne Mitrovich, and , Michael D. Vahey*,

{"title":"Genetically Recoding Respiratory Syncytial Virus to Visualize Nucleoprotein Dynamics and Virion Assembly","authors":"Margaret Dianne Mitrovich,  and , Michael D. Vahey*, ","doi":"10.1021/acsinfecdis.4c0032110.1021/acsinfecdis.4c00321","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00321https://doi.org/10.1021/acsinfecdis.4c00321","url":null,"abstract":"RNA viruses possess small genomes encoding a limited repertoire of essential and often multifunctional proteins. Although genetically tagging viral proteins provides a powerful tool for dissecting mechanisms of viral replication and infection, it remains a challenge. Here, we leverage genetic code expansion to develop a recoded strain of respiratory syncytial virus (RSV) in which the multifunctional nucleoprotein is site-specifically modified with a noncanonical amino acid. The resulting virus replicates exclusively in cells capable of amber stop codon suppression and is amenable to labeling with tetrazine-modified fluorophores, achieving high signal to background. Virus with labeled nucleoprotein remains functional, retaining ∼70% infectivity relative to unlabeled controls. We leverage this tool to visualize RSV assembly, capturing the transfer of nucleoprotein complexes from cytoplasmic condensates directly to budding viral filaments at the cell surface and to cytoplasmic compartments containing viral surface proteins. Collectively, these results suggest multiple pathways for RSV assembly and establish a framework that may be extended to other viral nucleoproteins.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 1","pages":"95–103 95–103"},"PeriodicalIF":4.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

nsP2 Protease Inhibitor Blocks the Replication of New World Alphaviruses and Offer Protection in Mice

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-12-31 DOI: 10.1021/acsinfecdis.4c0070110.1021/acsinfecdis.4c00701

Olawale S. Adeyinka, Michael D. Barrera, Damilohun S. Metibemu, Niloufar Boghdeh, Carol A. Anderson, Haseebullah Baha, Olamide Crown, John Adeolu Falode, Janard L. Bleach, Amanda R. Bliss, Tamia P. Hampton, Jane-Frances Chinenye Ojobor, Farhang Alem, Aarthi Narayanan and Ifedayo Victor Ogungbe*,

{"title":"nsP2 Protease Inhibitor Blocks the Replication of New World Alphaviruses and Offer Protection in Mice","authors":"Olawale S. Adeyinka, Michael D. Barrera, Damilohun S. Metibemu, Niloufar Boghdeh, Carol A. Anderson, Haseebullah Baha, Olamide Crown, John Adeolu Falode, Janard L. Bleach, Amanda R. Bliss, Tamia P. Hampton, Jane-Frances Chinenye Ojobor, Farhang Alem, Aarthi Narayanan and Ifedayo Victor Ogungbe*, ","doi":"10.1021/acsinfecdis.4c0070110.1021/acsinfecdis.4c00701","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00701https://doi.org/10.1021/acsinfecdis.4c00701","url":null,"abstract":"New World alphaviruses, including Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that cause disease in humans. These viruses are endemic to the western hemisphere, and disease in humans may lead to encephalitis and long-term neurological sequelae. There are currently no FDA-approved vaccines or antiviral therapeutics available for the prevention or treatment of diseases caused by these viruses. The alphavirus nonstructural protein 2 (nsP2) functions as a protease, which is critical for the establishment of a productive viral infection by enabling accurate processing of the nsP123 polyprotein. Owing to the essential role played by nsP2 in the alphavirus infectious process, it is also a valuable therapeutic target. In this article, we report the synthesis and evaluation of novel small molecule inhibitors that target the alphavirus nsP2 protease via a covalent mode of action. The two lead compounds demonstrated robust inhibition of viral replication in vitro. These inhibitors interfered with the processing of the nsP123 polyprotein as determined using VEEV TC-83 as a model pathogen and are active against EEEV and WEEV. The compounds were found to be nontoxic in two different mouse strains and demonstrated antiviral activity in a VEEV TC-83 lethal challenge mouse model. Cumulatively, the outcomes of this study provide a compelling rationale for the preclinical development of nsP2 protease inhibitors as direct-acting antiviral therapeutics against alphaviruses.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 1","pages":"181–196 181–196"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of CGS-15943 Adjunctives for the Disruption of Plasmid Maintenance in Multidrug Resistant E. coli

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-12-31 DOI: 10.1021/acsinfecdis.4c0058710.1021/acsinfecdis.4c00587

Mintesinot Kassu, Katelyn E. Zulauf, Jessica N. Ross, James E. Kirby and Roman Manetsch*,

{"title":"Development of CGS-15943 Adjunctives for the Disruption of Plasmid Maintenance in Multidrug Resistant E. coli","authors":"Mintesinot Kassu, Katelyn E. Zulauf, Jessica N. Ross, James E. Kirby and Roman Manetsch*, ","doi":"10.1021/acsinfecdis.4c0058710.1021/acsinfecdis.4c00587","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00587https://doi.org/10.1021/acsinfecdis.4c00587","url":null,"abstract":"Carbapenemase producing Enterobacterales (CPEs) represent a group of multidrug resistant pathogens for which few, if any, therapeutics options remain available. CPEs generally harbor plasmids that encode resistance to last resort carbapenems and many other antibiotics. We previously performed a high throughput screen to identify compounds that can disrupt the maintenance and replication of resistance conferring plasmids through use of a synthetic screening plasmid introduced into Escherichia coli K-12 tolC cells. Despite being identified as a potent and selective antiplasmid agent through this screening effort, CGS-15943 was inactive in wild-type E. coli, suggesting that it is susceptible to TolC-mediated efflux. Herein, a series of analogues were developed to confirm the activity of the triazoloquinazoline chemotype and overcome efflux observed in wild-type E. coli K-12. Two analogues demonstrated superior antiplasmid activity to CGS-15943 in E. coli tolC mutants, while one compound displayed moderate activity in wild-type E. coli at low concentrations.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 1","pages":"80–87 80–87"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancing Treatment for Leishmaniasis: From Overcoming Challenges to Embracing Therapeutic Innovations

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-12-31 DOI: 10.1021/acsinfecdis.4c0069310.1021/acsinfecdis.4c00693

Vishal Kumar Singh, Rahul Tiwari, Rajneesh, Awnish Kumar, Shashi Bhushan Chauhan, Medhavi Sudarshan, Sanjana Mehrotra, Vibhav Gautam, Shyam Sundar and Rajiv Kumar*,

{"title":"Advancing Treatment for Leishmaniasis: From Overcoming Challenges to Embracing Therapeutic Innovations","authors":"Vishal Kumar Singh, Rahul Tiwari,  Rajneesh, Awnish Kumar, Shashi Bhushan Chauhan, Medhavi Sudarshan, Sanjana Mehrotra, Vibhav Gautam, Shyam Sundar and Rajiv Kumar*, ","doi":"10.1021/acsinfecdis.4c0069310.1021/acsinfecdis.4c00693","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00693https://doi.org/10.1021/acsinfecdis.4c00693","url":null,"abstract":"Protozoan parasite infections, particularly leishmaniasis, present significant public health challenges in tropical and subtropical regions, affecting socio-economic status and growth. Despite advancements in immunology, effective vaccines remain vague, leaving drug treatments as the primary intervention. However, existing medications face limitations, such as toxicity and the rise of drug-resistant parasites. This presents an urgent need to identify new therapeutic targets for leishmaniasis treatment. Understanding the complex life cycle of Leishmania and its survival in host macrophages can provide insights into potential targets for intervention. Current treatments, including antimonials, amphotericin B, and miltefosine, are constrained by side effects, costs, resistance, and reduced efficacy. Exploring novel therapeutic targets within the parasite’s physiology, such as key metabolic enzymes or essential surface proteins, may lead to the development of more effective and less toxic drugs. Additionally, innovative strategies like drug repurposing, combination therapies, and nanotechnology-based delivery systems could enhance efficacy and combat resistance, thus improving anti-leishmanial therapies.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 1","pages":"47–68 47–68"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to “Porphyromonas gingivalis Promotes the Proliferation and Migration of Esophageal Squamous Cell Carcinoma through the miR-194/GRHL3/PTEN/Akt Axis”

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-12-26 DOI: 10.1021/acsinfecdis.4c0096410.1021/acsinfecdis.4c00964

Gaofeng Liang*, Haojie Wang, Hao Shi, Mengxi Zhu, Junling An, Yijun Qi, Jingxia Du, Yan Li and Shegan Gao*,

引用次数: 0

The Calcium-Dependent Antibiotics: Structure–Activity Relationships and Determination of Their Lipid Target

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-12-23 DOI: 10.1021/acsinfecdis.4c0081010.1021/acsinfecdis.4c00810

Jeremy Goodyear, Matthew Diamandas, Ryan Moreira and Scott D. Taylor*,

{"title":"The Calcium-Dependent Antibiotics: Structure–Activity Relationships and Determination of Their Lipid Target","authors":"Jeremy Goodyear, Matthew Diamandas, Ryan Moreira and Scott D. Taylor*, ","doi":"10.1021/acsinfecdis.4c0081010.1021/acsinfecdis.4c00810","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00810https://doi.org/10.1021/acsinfecdis.4c00810","url":null,"abstract":"The calcium-dependent antibiotics (CDAs) are a group of seven closely related membrane-active cyclic lipopeptide antibiotics (cLPAs) first isolated in the early 1980s from the fermentation broth of Streptomyces coelicolor. Their target was unknown, and the mechanism of action is uncertain. Herein, we report new routes for the synthesis of CDA4b and its analogues, explore the structure–activity relationships at its lipid tail and at positions 3, 9, and 11, and determine the CDAs’ lipid target. A CDA4b analogue in which the epoxide group in CDA’s 6-carbon lipid was replaced with a cyclopropyl group was 4-fold more active than CDA4b which suggests that the epoxide group is not acting as an electrophile to form a covalent bond with CDA4b’s target. The activity of this cyclopropyl analogue was significantly increased by extending the length of the lipid to 10 carbons. Studies with analogues in which d-HOAsn9 is replaced with d-Asn9 or d-Ser9 reveal that the hydroxy group of the d-HOAsn9 residue is not crucial for CDAs’ activity, while the amide moiety is important for activity. The l-Trp residue at position 11 could be replaced with l-kynurenine (l-Kyn) without significant loss of activity, while replacing the d-Trp residue at position 3 with d-Kyn resulted in a significant loss of activity. MIC values determined in the presence and absence of exogenous phospholipids and fluorescence spectroscopy studies using natural CDAs and CDA4b analogues containing Kyn and model membranes revealed that the CDAs’ primary lipid target is cardiolipin, a target that is unique among the broader class of known calcium-dependent antibiotics.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 1","pages":"226–237 226–237"},"PeriodicalIF":4.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143086099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Non-Polio Enterovirus Inhibitors: Scaffolds, Targets, and Potency─What’s New?

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-12-23 DOI: 10.1021/acsinfecdis.4c0060610.1021/acsinfecdis.4c00606

Hugo Fernando Georges Roux, Franck Touret, Pascal Rathelot, Pietro Sciò, Antonio Coluccia, Patrice Vanelle* and Manon Roche*,

引用次数: 0