ACS Infectious Diseases最新文献

{"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, Manidipa Banerjee","doi":"10.1021/acsinfecdis.4c00562","DOIUrl":"10.1021/acsinfecdis.4c00562","url":null,"abstract":"<p><p>Alphaviruses, a genus of vector-borne viruses in the <i>Togaviridae</i> 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.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"430-441"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913174","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}

{"title":"Potential of <i>Mycobacterium tuberculosis</i> Type II NADH-Dehydrogenase in Antitubercular Drug Discovery.","authors":"Pallavi Saha, Mohit Kumar, Deepak K Sharma","doi":"10.1021/acsinfecdis.4c01005","DOIUrl":"10.1021/acsinfecdis.4c01005","url":null,"abstract":"<p><p>The type II NADH-dehydrogenase enzyme in <i>Mycobacterium tuberculosis</i> plays a critical role in the efficient functioning of the oxidative phosphorylation pathway. It acts as the entry point for electrons in the electron transport chain, which is essential for fulfilling the energy requirements of both replicating and nonreplicating mycobacterial species. Due to the absence of the type II NADH-dehydrogenase enzyme in mammalian mitochondria, targeting the type II NADH-dehydrogenase enzyme for antitubercular drug discovery could be a vigilant approach. Utilizing type II NADH-dehydrogenase inhibitors in antitubercular therapy led to bactericidal response, even in monotherapy. However, the absence of the cryo-EM structure of <i>Mycobacterium tuberculosis</i> type II NADH-dehydrogenase has constrained drug discovery efforts to rely on high-throughput screening methods, limiting the use of structure-based drug discovery. Here, we have delineated the literature-reported <i>Mycobacterium tuberculosis</i> type II NADH-dehydrogenase inhibitors and the rationale behind selecting this specific enzyme for antitubercular drug discovery, along with shedding light on the architecture of the enzyme structure and functionality. The gap in the current research and future research direction for TB treatment have been addressed.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"398-412"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981973","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}

{"title":"Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches.","authors":"Juan Xiong, Hui Lu, Yuanying Jiang","doi":"10.1021/acsinfecdis.4c00657","DOIUrl":"10.1021/acsinfecdis.4c00657","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"305-322"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918808","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}

{"title":"Evaluation of Synthetic Peptides from <i>Schistosoma mansoni</i> ATP Diphosphohydrolase 1: In Silico Approaches for Characterization and Prospective Application in Diagnosis of Schistosomiasis.","authors":"Danielle Gomes Marconato, Beatriz Paiva Nogueira, Vinícius Carius de Souza, Rafaella Fortini Grenfell E Queiroz, Clovis R Nakaie, Eveline Gomes Vasconcelos, Priscila de Faria Pinto","doi":"10.1021/acsinfecdis.4c00697","DOIUrl":"10.1021/acsinfecdis.4c00697","url":null,"abstract":"<p><p>Schistosomiasis is the infection caused by <i>Schistosoma mansoni</i> and constitutes a worldwide public health problem. The parasitological recommended method and serological methods can be used for the detection of eggs and antibodies, respectively. However, both have limitations, especially in low endemicity areas. Thus, new approaches for the diagnosis of schistosomiasis are essential. In this study, a six-amino acid peptide and derived sequences from SmATPDase1 were synthesized for the evaluation of immunogenicity. SmATPDase1 is included in a protein group in <i>S. mansoni</i> tegument; therefore, its peptides could be potential candidates for diagnostic antigens. In the hypothetical SmATPDase1 three-dimensional structure, peptides are located in a region exposed and accessible to antibody binding. In addition, peptide amino acid sequences are conserved in the most relevant <i>Schistosoma</i> species and have low identity with human NTPDases isoforms. Swiss mice immunization resulted in significant anti-peptide polyclonal antibodies production, which recognized a 63 kDa protein in tegument and adult worm preparations. By immunofluorescence microscopy, polyclonal antibodies also identified this enzyme in cercariae. Sera of infected animals presented high seropositivity in ELISA-peptides, with an area under curve (AUC) greater than 0.96 for all peptides. In mice with low parasite burden, we observed a seropositivity AUC > 0.9. Reactivity in the prepatent period exhibited AUC values greater than 0.94 for all peptides. Anti-P1425 monoclonal antibodies were successfully produced, and mAbs recognized the integral protein in ELISA and Western blots. The data indicate that peptides from SmATPDase1 are potential biomarkers for schistosomiasis, and anti-peptide antibodies are interesting tools for the detection of the infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"463-473"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976763","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}

{"title":"Small and Versatile Cyclotides as Anti-infective Agents.","authors":"Elizabete de Souza Cândido, Liryel Silva Gasparetto, Livia Veiga Luchi, João Pedro Farias Pimentel, Marlon Henrique Cardoso, Maria Lígia Rodrigues Macedo, Cesar de la Fuente-Nunez, Octávio Luiz Franco","doi":"10.1021/acsinfecdis.4c00957","DOIUrl":"10.1021/acsinfecdis.4c00957","url":null,"abstract":"<p><p>Plants provide an abundant source of potential therapeutic agents, including a diverse array of compounds, such as cyclotides, which are peptides known for their antimicrobial activity. Cyclotides are multifaceted molecules with a wide range of biological activities. Their unique topology forms a head-to-tail cyclic structure reinforced by a cysteine knot, which confers chemical and thermal stability. These molecules can directly target membranes of infectious agents by binding to phosphatidylethanolamine in lipid membranes, leading to membrane permeabilization. Additionally, they function as carriers and cell-penetrating molecules, demonstrating antiviral, antibacterial, antifungal, and nematicidal properties. The structure of cyclotides is also amenable to chemical synthesis, facilitating drug design through residue substitutions or grafting of bioactive epitopes within the cyclotide scaffold to enhance peptide stability. In this review, we explore the multifunctionality of these biomolecules as anti-infective agents, emphasizing their potential as a novel class of antimicrobial drugs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"386-397"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021289","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}

{"title":"Metabolic Flexibility and Essentiality of the Tricarboxylic Acid Cycle in <i>Plasmodium</i>.","authors":"Arpitha Suryavanshi, Anusha Chandrashekarmath, Nivedita Pandey, Hemalatha Balaram","doi":"10.1021/acsinfecdis.4c00788","DOIUrl":"10.1021/acsinfecdis.4c00788","url":null,"abstract":"<p><p>The complete tricarboxylic acid (TCA) cycle, comprising a series of 8 oxidative reactions, occurs in most eukaryotes in the mitochondria and in many prokaryotes. The net outcome of these 8 chemical reactions is the release of the reduced electron carriers NADH and FADH₂, water, and carbon dioxide. The parasites of the <i>Plasmodium spp</i>., belonging to the phylum Apicomplexa, have all the genes for a complete TCA cycle. The parasite completes its life cycle across two hosts, the insect vector mosquito and a range of vertebrate hosts including humans. As the niches that the parasite invades and occupies in the two hosts vary dramatically in their biochemical nature and availability of nutrients, the parasite's energy metabolism has been accordingly adapted to its host environment. One such pathway that shows extensive metabolic plasticity in parasites of the <i>Plasmodium spp</i>. is the TCA cycle. Recent studies using isotope-tracing targeted-metabolomics have highlighted conserved and parasite-specific features in the TCA cycle. This Review provides a comprehensive summary of what is known of this central pathway in the <i>Plasmodium spp</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"335-349"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044867","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}

{"title":"Ten Years of <i>ACS Infectious Diseases</i> - A Celebration of Excellence.","authors":"Jayanta Haldar","doi":"10.1021/acsinfecdis.5c00050","DOIUrl":"10.1021/acsinfecdis.5c00050","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"271-276"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062132","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}

{"title":"Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.","authors":"Mark J Mitton-Fry, Jason E Cummings, Yanran Lu, Jillian F Armenia, Jo Ann W Byl, Alexandria A Oviatt, Allison A Bauman, Gregory T Robertson, Neil Osheroff, Richard A Slayden","doi":"10.1021/acsinfecdis.4c00743","DOIUrl":"10.1021/acsinfecdis.4c00743","url":null,"abstract":"<p><p>Developing new classes of drugs that are active against infections caused by <i>Mycobacterium tuberculosis</i> is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.125 μg/mL against both drug-susceptible and drug-resistant strains of <i>M. tuberculosis</i>. These lead compounds also demonstrated antitubercular activity in ex vivo studies using infected THP-1 macrophages with minimal cytotoxicity in THP-1, HeLa, and HepG2 cells (IC₅₀ ≥ 128 μg/mL). The molecular target of the lead compounds was validated through biochemical studies of select analogues with purified <i>M. tuberculosis</i> gyrase and the generation of resistant mutants. The lead compounds were assessed in combination with bedaquiline and pretomanid to determine the clinical potential, and the select lead (<b>158</b>) demonstrated in vivo efficacy in an acute model of TB infection in mice, reducing the lung bacterial burden by approximately 3 log₁₀ versus untreated control mice. The advancement of DNA gyrase inhibitors expands the field of innovative therapies for tuberculosis and may offer an alternative to fluoroquinolones in future therapeutic regimens.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"474-482"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962017","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}

{"title":"Virtual Screening Uncovers DspS Activators That Disperse <i>Pseudomonas aeruginosa</i> Biofilms.","authors":"Christabel Ming Ming Koh, Siaw San Hwang, Bee Theng Lau, Enzo A Palombo, Irine Runnie Henry Ginjom, Christopher Heng Xuan Ha, Taufiq Rahman, Xavier Chee Wezen","doi":"10.1021/acsinfecdis.4c00549","DOIUrl":"10.1021/acsinfecdis.4c00549","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is the predominant bacterium found in many chronic biofilm infections. Over the past few decades, biofilm-related infections have posed a significant challenge to medical practice due to the increasing emergence of multidrug resistance. <i>Cis</i>-2-decenoic acid (CDA), a small molecule found in <i>P. aeruginosa</i>, has been shown to disperse biofilms formed by various bacteria and to work in synergy with common antibiotics. Despite that, the binding mechanism between CDA and the predicted cyclases/histidine kinases associated sensory extracellular (CHASE) domain of sensor protein DspS remains unknown in the absence of a crystallized protein structure. Moreover, the therapeutic potential of CDA is limited by its susceptibility to oxidative degradation and isomerization. In this work, we propose a structural model for the DspS CHASE domain. The resulting model displays an overall topology reminiscent of the sensor protein PcrK in <i>Xanthomonas campestris</i>. Through molecular dynamics simulations, a stable potential binding site for CDA was further identified. Virtual screening against the predicted site of DspS CHASE using our developed pipeline discovered two promising compounds, compounds <b>2</b> and <b>9</b>, capable of dislodging 7-day <i>P. aeruginosa</i> biofilms at 50 μM without affecting bacterial growth. These compounds also enhanced the effects of ciprofloxacin against <i>P. aeruginosa</i>, reduced the survival of dispersed cells, and increased the expression of matrix-degrading enzyme genes <i>pelA</i>, <i>pslG</i>, and <i>eddA</i>. This study provides insights into CDA recognition by DspS and represents the first large-scale effort to uncover first-in-class DspS activators. At the same time, this work also underscores the effectiveness of a computational-aided drug discovery process in finding new activators, even without a known protein structure.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"413-429"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453227","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}

{"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, Margaret G Petroff","doi":"10.1021/acsinfecdis.4c00641","DOIUrl":"10.1021/acsinfecdis.4c00641","url":null,"abstract":"<p><p>Group B <i>Streptococcus</i> (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 (<i>p</i> < 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.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"453-462"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412306","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}