ACS Infectious Diseases最新文献

{"title":"Decoding the Role of Antimicrobial Peptides in the Fight against <i>Mycobacterium tuberculosis</i>.","authors":"Sapna Saini, Sunny Pal, Rashmi Sharma","doi":"10.1021/acsinfecdis.4c00806","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00806","url":null,"abstract":"<p><p>Tuberculosis (TB), a leading infectious disease caused by the pathogen <i>Mycobacterium tuberculosis</i>, poses a significant treatment challenge due to its unique characteristics and resistance to existing drugs. The conventional treatment regimens, which are lengthy and involve multiple drugs, often result in poor patient adherence and subsequent drug resistance, particularly with multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. This highlights the urgent need for novel anti-TB therapies and new drug targets. Antimicrobial peptides (AMPs), which are natural host defense molecules present in all living organisms, offer a promising alternative to traditional small-molecule drugs. AMPs have several advantages, including their broad-spectrum activity and the potential to circumvent existing resistance mechanisms. However, their clinical application faces challenges such as stability, delivery, and potential toxicity. This review aims to provide essential information on AMPs, including their sources, classification, mode of action, induction within the host under stress, efficacy against <i>M. tuberculosis</i>, clinical status and hurdles to their use. It also highlights future research directions to address these challenges and advance the development of AMP-based therapies for TB.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051040","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-27","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":"Advantages and Challenges of Using Antimicrobial Peptides in Synergism with Antibiotics for Treating Multidrug-Resistant Bacteria.","authors":"Regina Meneses Gonçalves, Bruna Estéfani Dutra Monges, Karen Garcia Nogueira Oshiro, Elizabete de Souza Cândido, João Pedro Farias Pimentel, Octávio Luiz Franco, Marlon Henrique Cardoso","doi":"10.1021/acsinfecdis.4c00702","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00702","url":null,"abstract":"<p><p>Multidrug-resistant bacteria (MDR) have become a global threat, impairing positive outcomes in many cases of infectious diseases. Treating bacterial infections with antibiotic monotherapy has become a huge challenge in modern medicine. Although conventional antibiotics can be efficient against many bacteria, there is still a need to develop antimicrobial agents that act against MDR bacteria. Bioactive peptides, particularly effective against specific types of bacteria, are recognized for their selective and effective action against microorganisms and, at the same time, are relatively safe and well tolerated. Therefore, a growing number of works have proposed the use of antimicrobial peptides (AMPs) in synergism with commercial antibiotics as an alternative therapeutic strategy. This review provides an overview of the critical parameters for using AMPs in synergism with antibiotics as well as addressing the strengths and weaknesses of this combination therapy using <i>in vitro</i> and <i>in vivo</i> models of infection. We also cover the challenges and perspectives of using this approach for clinical practice and the advantages of applying artificial intelligence strategies to predict the most promising combination therapies between AMPs and antibiotics.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035349","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":"Elucidation of the Glycan Structure of the b-type Flagellin of <i>Pseudomonas aeruginosa</i> PAO1.","authors":"Paul J Hensbergen, Loes van Huijkelom, Jordy van Angeren, Arnoud H de Ru, Bart Claushuis, Peter A van Veelen, Wiep Klaas Smits, Jeroen Corver","doi":"10.1021/acsinfecdis.4c00896","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00896","url":null,"abstract":"<p><p>Flagella are essential for motility and pathogenicity in many bacteria. The main component of the flagellar filament, flagellin (FliC), often undergoes post-translational modifications, with glycosylation being a common occurrence. In <i>Pseudomonas aeruginosa</i> PAO1, the b-type flagellin is <i>O</i>-glycosylated with a structure that includes a deoxyhexose, a phospho-group, and a previous unknown moiety. This structure resembles the well-characterized glycan (Type A) in <i>Clostridioides difficile</i> strain 630, which features an <i>N</i>-acetylglucosamine linked to an <i>N</i>-methylthreonine via a phosphodiester bond. This study aimed to characterize the b-type glycan structure in <i>Pseudomonas aeruginosa</i> PAO1 using a set of mass spectrometry experiments. For this purpose, we used wild-type <i>P. aeruginosa</i> PAO1 and several gene mutants from the b-type glycan biosynthetic cluster. Moreover, we compared the mass spectrometry characteristics of the b-type glycan with those of <i>in vitro</i> modified Type A-peptides from <i>C. difficile</i> strain 630Δ<i>erm</i>. Our results demonstrate that the thus far unknown moiety of the b-type glycan in <i>P. aeruginosa</i> consists of an <i>N,N</i>-dimethylthreonine. These data allowed us to refine our model of the flagellin glycan biosynthetic pathway in both <i>P. aeruginosa</i> PAO1 and <i>C. difficile</i> strain 630.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031496","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":"Building Spatiotemporal Understanding of <i>Mycobacterium tuberculosis</i>-Host Interactions.","authors":"Anna-Lisa E Lawrence, Shumin Tan","doi":"10.1021/acsinfecdis.4c00840","DOIUrl":"10.1021/acsinfecdis.4c00840","url":null,"abstract":"<p><p>Heterogeneity during <i>Mycobacterium tuberculosis</i> (Mtb) infection greatly impacts disease outcome and complicates treatment. This heterogeneity encompasses many facets, spanning local differences in the host immune response to Mtb and the environment experienced by the bacterium, to nonuniformity in Mtb replication state. All of these facets are interlinked and each can affect Mtb susceptibility to antibiotic treatment. In-depth spatiotemporal understanding of Mtb-host interactions is thus critical to both fundamental comprehension of Mtb infection biology and for the development of effective therapeutic regimens. Such spatiotemporal understanding dictates the need for analysis at the single bacterium/cell level in the context of intact tissue architecture, which has been a significant technical challenge. Excitingly, innovations in spatial single cell methodology have opened the door to such studies, beginning to illuminate aspects ranging from intergranuloma differences in cellular composition and phenotype, to sublocation differences in Mtb physiology and replication state. In this perspective, we discuss recent studies that demonstrate the potential of these methodological advancements to reveal critical spatiotemporal insight into Mtb-host interactions, and highlight future avenues of research made possible by these advances.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027433","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Human PIM Kinase Inhibitors as a Class of Anthelmintic Drugs to Treat Intestinal Nematode Infections.","authors":"Victoria Banas, Mostafa A Elfawal, Bruce A Rosa, Matthew Mahoney, Jacquelyn Kauffman, Emily Goetz, Paulina Chen, Raffi V Aroian, Makedonka Mitreva, James W Janetka","doi":"10.1021/acsinfecdis.4c00864","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00864","url":null,"abstract":"<p><p>Soil-transmitted helminth (STH) infections affect one-fourth of the global population and pose a significant threat to human and animal health, with limited treatment options and emerging drug resistance. <i>Trichuris trichiura</i> (whipworm) stands out as a neglected disease, necessitating new drugs to address this unmet medical need. We discovered that several different chemical series of related human Provirus Integration sites for Moloney murine leukemia virus (PIM) family kinase inhibitors possess potent anthelmintic activity by using whole-worm motility assays. Systematic structure-activity relationship (SAR) studies based on the <i>pan</i>-PIM kinase inhibitor CX-6258 were conducted to identify compounds displaying improved <i>in vitro</i> motility inhibition of both adult hookworm (<i>Ancylostoma ceylanicum</i>) and adult whipworm (<i>Trichuris muris</i>) nematodes. A broad kinase selectivity screen of >450 human kinases confirms PIM1 kinase and others as potential targets for CX-6258 and analogues thereof. In addition, we demonstrated that CX-6258 significantly reduced worm burden and egg counts in the <i>T. muris</i> infection model of mice, establishing it as a new oral small molecule anthelmintic therapeutic.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995991","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":"Multifunctional Mycobacterial Topoisomerases with Distinctive Features.","authors":"Iqball Faheem, Valakunja Nagaraja","doi":"10.1021/acsinfecdis.4c00880","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00880","url":null,"abstract":"<p><p>Tuberculosis (TB) continues to be a major cause of death worldwide despite having an effective combinatorial therapeutic regimen and vaccine. Being one of the most successful human pathogens, <i>Mycobacterium tuberculosis</i> retains the ability to adapt to diverse intracellular and extracellular environments encountered by it during infection, persistence, and transmission. Designing and developing new therapeutic strategies to counter the emergence of multidrug-resistant and extensively drug-resistant TB remains a major task. DNA topoisomerases make up a unique class of ubiquitous enzymes that ensure steady-state level supercoiling and solve topological problems occurring during DNA transactions in cells. They continue to be attractive targets for the discovery of novel classes of antibacterials and to develop better molecules from existing drugs by virtue of their reaction mechanism. The limited repertoire of topoisomerases in <i>M. tuberculosis</i>, key differences in their properties compared to topoisomerases from other bacteria, their essentiality for the pathogen's survival, and validation as candidates for drug discovery provide an opportunity to exploit them in drug discovery efforts. The present review provides insights into their organization, structure, function, and regulation to further efforts in targeting them for new inhibitor discovery. First, the structure and biochemical properties of DNA gyrase and Topoisomerase I (TopoI) of mycobacteria are described compared to the well-studied counterparts from other bacteria. Next, we provide an overview of known inhibitors of DNA gyrase and emerging novel bacterial topoisomerase inhibitors (NBTIs). We also provide an update on TopoI-specific compounds, highlighting mycobacteria-specific inhibitors.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995994","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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-15","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}