ACS Infectious Diseases最新文献

{"title":"A Strain-Specific Clumping Mechanism Enables <i>Staphylococcus aureus</i> ST88 to Circumvent the Host Neutrophil Response.","authors":"Vandanashree Muralidharan, Rakesh Kumar Pradhan, Savitha Nadig, Anitha N Bavikatte, Sneha Murthy, Mitali Shah, Shruthi Sridhar Vembar, Siddharth Jhunjhunwala, Balasubramanian Gopal","doi":"10.1021/acsinfecdis.4c01009","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01009","url":null,"abstract":"<p><p>Community-associated methicillin-resistant <i>Staphylococcus aureus</i> strains often demonstrate enhanced virulence, with different strains eliciting varied immune responses in humans. The factors that enable some <i>S. aureus</i> strains to evade killing by immune cells remain unclear. Here, we describe studies designed to understand <i>ex vivo</i> intracellular survival assays that revealed that while a well-characterized MRSA ST8 strain (USA300) was susceptible to phagocytic clearance, a genotypically similar MRSA ST88 strain (LVP-7) effectively evaded neutrophil killing. A pronounced enhancement in neutrophil lysis upon ST88 infection suggests that ST88 can infect polymorphonuclear human neutrophils yet circumvent phagocytosis-associated killing. Both ST8 and ST88 strains show a similar response to extracellular stress elicited by H₂O₂, HOCl, or NO. Host bactericidal mechanisms, such as the release of reactive oxygen species, myeloperoxidases, and elastases, were similar when infected with either strain. The transcriptome profile of ST88 upon phagocytosis at different stages of infection alongside a comparison of the phenotypic traits of ST8 and ST88 revealed factors that could potentially rationalize ST88's evasion of killing by neutrophils. Upon phagocytosis, the ST88 transcriptome showed distinct changes in the levels of the quorum sensing accessory gene regulator (Agr). Confocal imaging revealed that the ST88 strain clusters more with higher bacteria per infected neutrophil than the ST8 strain. A pronounced reduction in ST88 clumping was seen upon the addition of the cognate autoinducing peptide AIP-III, consistent with the premise that the Agr mechanism plays a role in the evasion of neutrophil-mediated killing by the ST88 strain. It thus appears likely that clumping, modulated by quorum sensing, provides a route for this <i>S. aureus</i> strain to evade the human innate immune response.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641182","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":"AI Drug Discovery: Expanding the Horizons of Infectious Disease Therapeutics.","authors":"Marta Bon, Fraser Cunningham, Jyoti Chauhan, Brian Lu, Sid Jain, Brandon Probst, Ian Goodfellow, Alberto Bresciani","doi":"10.1021/acsinfecdis.5c00462","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00462","url":null,"abstract":"<p><p>Drug discovery and development for infectious diseases has transformed from phenotypic screening to rational design, and now embracing artificial intelligence (AI) to accelerate and optimize therapeutic development. We describe our use of AI to analyze vast and diverse data sets to generate therapeutic hypotheses and identify novel drug targets. We discuss generative design, active learning and automation. Finally we cover the use of AI in development. We believe that decoding biology and industrializing discovery through AI and automation is revolutionizing drug discovery in general, and has the potential to deliver improved patient outcomes and global health benefits in infectious diseases.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641183","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":"Extracellular vesicles from Distinct <i>Histoplasma capsulatum</i> Strains Modulate Phagocyte Function and Promote Fungal Persistence.","authors":"Taiane N Souza, Alessandro F Valdez, Ana Claudia G Zimbres, Bianca A G Sena, Flavia C G Reis, Marcio L Rodrigues, Daniel Zamith-Miranda, Allan J Guimarães, Alessandra A Filardy, Joshua D Nosanchuk, Leonardo Nimrichter","doi":"10.1021/acsinfecdis.5c00378","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00378","url":null,"abstract":"<p><p>Fungal extracellular vesicles (EVs) are lipid-bilayer compartments that transport a wide range of molecules, including proteins, polysaccharides, pigments, small metabolites, lipids, and RNA. In fungal pathogens, EVs harbor virulence factors as well as antigenic determinants that modulate the host immune response. In this work, we investigated the modulatory effects of EVs released by two phenotypically and genotypically distinct strains of <i>Histoplasma capsulatum</i> (G-217B and G-184A) on bone marrow-derived macrophages (BMDMs) and bone marrow-derived dendritic cells (BMDCs). Both host cells internalized <i>H. capsulatum</i> EVs, which appeared to elicit distinct functional responses. Treatment of BMDMs with EVs from either strain (EV_HcG-184A and EV_HcG-217B) increased IL-6 production with no significant changes in IL-10 levels. In contrast, BMDCs exposed with both EVs exhibited elevated levels of IL-6 and IL-10. Although EV treatment led to increased inducible nitric oxide synthase expression in BMDMs, it did not stimulate NO production. Remarkably, both EVs reduced the metabolic activity of phagocytes. Overnight exposure to EV_HcG-217B enhanced the phagocytosis of <i>H. capsulatum</i> yeasts by BMDMs; however, the phagolysosomal fusion was not affected. Notably, in DCs, EV_HcG-217B enhanced both the uptake and the viability of G-217B yeasts. Furthermore, incubation of <i>H. capsulatum</i> with its respective EVs promoted fungal growth, suggesting a self-stimulatory mechanism that may contribute to fungal persistence within host cells. Taken together, our results support the idea that <i>H. capsulatum</i> EVs are modulators of host-pathogen interaction, influencing phagocyte function and potentially contributing to fungal virulence.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144624908","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":"","authors":"Fangfeng Yuan,&nbsp;Junru Cui,&nbsp;Tianlei Wang,&nbsp;Jane Qin,&nbsp;Ju Hyeong Jeon,&nbsp;Huiming Ding,&nbsp;Charles A. Whittaker,&nbsp;Renhuan Xu,&nbsp;Hong Cao and Jianzhu Chen*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595014","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":"","authors":"Maria Cidinaria Silva Alves*,&nbsp;Mireli Santana Rego,&nbsp;Ruana Carolina Cabral da Silva,&nbsp;Rousilândia de Araújo Silva,&nbsp;Igor Eduardo Silva Arruda,&nbsp;Sérgio de Sá Leitão Paiva-Júnior and Valdir de Queiroz Balbino*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00250","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595021","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":"Halogenated Sulfono-γ-AApeptides Modified Cationic AMPs Have Enhanced Stability and Therapeutic Potential against Clinically Important MDR Infections.","authors":"Xiaomin Guo, Yingying An, Tiantian Yan, Yue Jia, Ruoyan Jiao, Xinyu Cai, Weili Yang, Guangjun Bao, Wangsheng Sun, Wenle Yang, Ningning Lu, Junqiu Xie","doi":"10.1021/acsinfecdis.5c00312","DOIUrl":"10.1021/acsinfecdis.5c00312","url":null,"abstract":"<p><p>Antimicrobial peptides have garnered increasing attention and are anticipated to address the growing crisis of antibiotic resistance. However, their inadequate proteolytic stability poses significant challenges for clinical development. In this study, we present a highly effective strategy to overcome the limitations by introducing multiple halogenated sulfono-γ-AApeptides into cationic AMP Feleucin-K3. Surprisingly, K162 and K174, which feature sulfono-γ-AApeptide modifications containing iodinated or trifluoromethyl groups, exhibit powerful antibacterial and antibiofilm activities, while having significantly improved stability. Furthermore, they exhibited low resistance tendencies and were less susceptible to cross-resistance in comparison to antibiotics. Additionally, the two analogs exhibited superior safety and therapeutic potential compared to polymyxin B against pneumonia induced by multidrug-resistant <i>P. aeruginosa</i>. For skin- and catheter-biofilm-related infections caused by MRSA, K162, and K174 displayed comparable therapeutic effects compared to vancomycin. In conclusion, K162 and K174 are considered novel antimicrobial alternatives to combat multidrug-resistant bacterial infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"2018-2036"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281667","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":"Inhibitors of the Bacterioferritin Ferredoxin Complex Dysregulate Iron Homeostasis and Kill <i>Acinetobacter baumannii</i> and Biofilm-Embedded <i>Pseudomonas aeruginosa</i> Cells.","authors":"Alexanndra M Behm, Huili Yao, Emmanuel C Eze, Suliat A Alli, Simon D P Baugh, Ebenezer Ametsetor, Kendall M Powell, Kevin P Battaile, Steve Seibold, Scott Lovell, Richard A Bunce, Allen B Reitz, Mario Rivera","doi":"10.1021/acsinfecdis.5c00209","DOIUrl":"10.1021/acsinfecdis.5c00209","url":null,"abstract":"<p><p>In <i>Pseudomonas aeruginosa</i>, the iron storage protein bacterioferritin (Bfr) contributes to buffering cytosolic free iron concentrations by oxidizing Fe²⁺ and storing the resultant Fe³⁺ in its internal cavity, and by forming a complex with a cognate ferredoxin (Bfd) to reduce the stored Fe³⁺ and mobilize Fe²⁺ to the cytosol. Small molecule derivatives of 4-aminoisoindoline-1,3-dione designed to bind <i>P. aeruginosa</i> Bfr (Pa Bfr) at the Bfd binding site accumulate in the <i>P. aeruginosa</i> cell, block the Pa Bfr-Bfd complex, inhibit iron mobilization from Pa Bfr, elicit an iron starvation response, are bacteriostatic to planktonic cells, and are bactericidal to biofilm-entrenched cells. A structural alignment of Pa Bfr and <i>Acinetobacter baumannii</i> Bfr (Ab Bfr) showed strong conservation of the Bfd binding site on Ab Bfr. Accordingly, the small molecule inhibitors of the Pa Bfr-Bfd complex accumulate in the <i>A. baumannii</i> cells, elicit an iron starvation response, are bactericidal to planktonic cells, and exhibit synergy with existing antibiotics. These findings indicate that the inhibition of iron mobilization from Bfr may be an antimicrobial strategy applicable to other Gram-negative pathogens.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1983-1993"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256629","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":"Single-Sample Melt-Based Screening for Rifampicin Susceptibility in the Emerging Mutation Hotspot at <i>rpoB</i> Codon 491.","authors":"Nicole A Malofsky, Swayashreyee B Dhungel, Megan E Pask, Frederick R Haselton","doi":"10.1021/acsinfecdis.5c00150","DOIUrl":"10.1021/acsinfecdis.5c00150","url":null,"abstract":"<p><p>Based on sequencing data, mutations at <i>rpoB</i> codon 491 of<i>Mycobacterium tuberculosis</i>are associated with rifampicin resistance, but current commercial and WHO-endorsed genotypic tests fail to detect them. As a result, resistant infections go untreated, driving transmission and multidrug resistance. A real-time PCR assay by André et al. specifically screens for I491F but omits other codon 491 mutations. To address this gap, a single-sample screening method using asymmetric PCR followed by melt analysis was developed for the three sequence-identified variants, I491F/N/M. Each sample contained a melt probe matching the susceptible sequence, which, after asymmetric PCR spanning codon 491, hybridized with the excess strand to form a duplex. The duplex's melt temperature (<i>T</i>_m) was then measured. To enable single-sample classification, each reaction also included double-stranded L-DNA identical to the probe and wild-type PCR product duplex. Susceptibility was determined by the within-sample <i>T</i>_m difference between the probe-product and L-DNA duplexes. The approach was evaluated and compared to the André assay across two calibrated PCR instruments using synthetic <i>rpoB</i> wild-type and variant sequences. As expected, the André assay distinguished wild-type from I491F samples but misclassified I491N and I491M samples based on multisample <i>T</i>_m comparison. In contrast, our single-sample classification strategy used within-sample <i>T</i>_m differences, classifying samples as rifampicin-susceptible when the within-sample <i>T</i>_m difference was less than 0.83 °C. With this approach, the method achieved 100% sensitivity and 100% specificity across both PCR instruments. Although demonstrated for <i>rpoB</i> codon 491, this assay design is readily adaptable to any other sequence-identified, clinically significant mutation hotspot.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1934-1943"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315503","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":"","authors":"Xiaomin Guo,&nbsp;Yingying An,&nbsp;Tiantian Yan,&nbsp;Yue Jia,&nbsp;Ruoyan Jiao,&nbsp;Xinyu Cai,&nbsp;Weili Yang,&nbsp;Guangjun Bao,&nbsp;Wangsheng Sun,&nbsp;Wenle Yang,&nbsp;Ningning Lu* and Junqiu Xie*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595010","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":"","authors":"Addison M. Duda,&nbsp;Helena R. Ma,&nbsp;César A. Villalobos,&nbsp;Sophia A. Kuhn,&nbsp;Sarah S. Angle,&nbsp;Katherine He,&nbsp;Abigail C. Jackson,&nbsp;Christine M. Suh,&nbsp;Elena A. Puccio,&nbsp;Deverick J. Anderson,&nbsp;Vance G. Fowler,&nbsp;Lingchong You and Katherine J. Franz*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595016","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}