ACS Infectious Diseases最新文献

{"title":"Identification of Cysteine Metabolism Regulator (CymR)-Derived Pentapeptides as Nanomolar Inhibitors of <i>Staphylococcus aureus</i> <i>O</i>-Acetyl-l-serine Sulfhydrylase (CysK).","authors":"Jordan L Pederick, Bethiney C Vandborg, Amir George, Hannah Bovermann, Jeffrey M Boyd, Joel S Freundlich, John B Bruning","doi":"10.1021/acsinfecdis.4c00832","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00832","url":null,"abstract":"<p><p>The pathway of bacterial cysteine biosynthesis is gaining traction for the development of antibiotic adjuvants. Bacterial cysteine biosynthesis is generally facilitated by two enzymes possessing <i>O</i>-acetyl-l-serine sulfhydrylases (OASS), CysK and CysM. In <i>Staphylococcus aureus</i>, there exists a single OASS homologue, <i>Sa</i>CysK. Knockout of <i>Sa</i>CysK was found to increase sensitivity to oxidative stress, making it a relevant target for inhibitor development. <i>Sa</i>CysK also forms two functional complexes via interaction with the preceding enzyme in the pathway serine acetyltransferase (CysE) or the transcriptional regulator of cysteine metabolism (CymR). These interactions occur through insertion of a C-terminal peptide of CysE or CymR into the active site of <i>Sa</i>CysK, inhibiting OASS activity, and therefore represent an excellent starting point for developing <i>Sa</i>CysK inhibitors. Here, we detail the characterization of CysE and CymR-derived C-terminal peptides as inhibitors of <i>Sa</i>CysK. Using a combination of X-ray crystallography, surface plasmon resonance, and enzyme inhibition assays, it was determined that the CymR-derived decapeptide forms extensive interactions with <i>Sa</i>CysK and acts as a potent inhibitor (<i>K</i>_D = 25 nM; IC₅₀ = 180 nM), making it a promising lead for the development of <i>Sa</i>CysK inhibitors. To understand the determinants of this high-affinity interaction, the structure-activity relationships of 16 rationally designed peptides were also investigated. This identified that the C-terminal pentapeptide of CymR facilitates the high-affinity interaction with <i>Sa</i>CysK and that subtle structural modification of the pentapeptide is possible without impacting potency. Ultimately, this work identified CymR pentapeptides as a promising scaffold for the development of antibiotic adjuvants targeting <i>Sa</i>CysK.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862502","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":"Shape and Size Dependent Antimicrobial and Anti-biofilm Properties of Functionalized MoS₂.","authors":"Navjot Kaur, Mrinmoy De","doi":"10.1021/acsinfecdis.4c00860","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00860","url":null,"abstract":"<p><p>Bacterial resistance, accelerated by the misuse of antibiotics, remains a critical concern for public health, promoting an ongoing exploration for cost-effective and safe antibacterial agents. Recently, there has been significant focus on various nanomaterials for the development of alternative antibiotics. Among these, molybdenum disulfide (MoS₂) has gained attention due to its unique chemical, physical, and electronic properties, as well as its semiconducting nature, biocompatibility, and colloidal stability, positioning it as a promising candidate for biomedical research. The impact of the shape and size of MoS₂ nanomaterials on the antibacterial activity remains largely unexplored. In this study, we investigated the effect of the shape and size of MoS₂ nanomaterials, such as quantum dots, nanoflowers, and nanosheets, on antimicrobial and anti-biofilm activity. As we had established earlier, functionalization with positively charged thiol ligands can enhance colloidal stability, biocompatibility, and antibacterial efficacy; we functionalized all targeted nanomaterials. Our results revealed that functionalized MoS₂ quantum dots (F-MQDs) exhibited superior activity compared to functionalized MoS₂ nanoflowers (F-MNFs) and functionalized MoS₂ nanosheets (F-MNSs) against <i>Staphylococcus aureus</i> (SA), both drug-resistant (methicillin) and nonresistant strains. We observed very low minimum inhibitory concentration (MIC, 30 ng/mL) for F-MQDs. The observed trend in antibacterial efficacy was as follows: F-MQDs > F-MNFs ≥ F-MNSs. We explored the relevant mechanism related to the antibacterial activity where the balance between membrane depolarization and internalization plays the determining role. Furthermore, F-MQDs show enhanced anti-biofilm activity compared to F-MNFs and F-MNSs against mature MRSA biofilms. Due to the superior antibacterial and anti-biofilm activity of F-MQDs, we extended their application to wound healing. This study will help us to develop other appropriate surface modified nanomaterials for antibacterial and anti-biofilm activity for further applications such as antibacterial coatings, water disinfection, and wound healing.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862504","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":"Invention of Enmetazobactam: An Indian Triumph in Antimicrobial Drug Discovery.","authors":"Maneesh Paul-Satyaseela","doi":"10.1021/acsinfecdis.4c00982","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00982","url":null,"abstract":"<p><p>The discovery of antimicrobials was an inflection point in human existence since it contributed enormously to the extension of the human lifespan. Among others, the invention of Enmetazobactam marks a significant milestone in the field of antimicrobial development, especially for India. It is a novel beta-lactamase inhibitor invented by scientists at Orchid Pharma in Chennai, India, and has garnered international attention for its potential to address antimicrobial resistance. It became the first new chemical entity invented in India, clinically developed by Allecra Therapeutics GmbH, to be approved by the U.S. Food & Drug Administration, with additional approvals from the European Medical Agency, the U.K.'s Medicine & Healthcare Products Regulatory Agency, and the Drug Controller General of India.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862503","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 Exosomal Proteins as Potential Biomarkers from RBC Stages of <i>Plasmodium falciparum</i> 3D7.","authors":"Urja Joshi, Sumedha Shah, Sharad Gupta, Linz-Buoy George, Hyacinth Highland","doi":"10.1021/acsinfecdis.4c00513","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00513","url":null,"abstract":"<p><p>Falciparum malaria relies extensively on cell-to-cell communication, and earlier research on the function of exosomal proteins derived from infected red blood cells (iRBCs) has been classified into numerous important roles. In this study, the exosomes were derived from <i>Pf3D7</i>-iRBCs cultured in vitro during synchronized trophozoite stages. The isolated exosomes were assessed using NTA, FE-SEM, and flow cytometry. Our study reported heterogeneous populations of exosomes during the infection. Additionally, label-free quantification based on LC/MS-MS for protein profiling revealed the presence of both parasitic and host (RBC) proteins; out of a total of 124 proteins detected, 20 <i>Pf3D7</i> proteins and 80 RBC proteins were identified. Exosomal RBC protein expression is different in cRBCs-Exo and iRBCs-Exo, which shows how the parasite and RBCs interact with each other. Functional classification reported that the majority of these <i>Pf3D7</i> proteins are uncharacterized with unknown functions, few of which are involved in biological processes such as regulation of complement activation, response to external stimuli, immune system-mediated signaling pathway, protein processing, etc. Hence, studying these exosomal proteins and comparing them to previous research has helped us understand how exosomes help cells to communicate in malaria. It may also reveal new potential biomarkers for diagnostic methods or therapies for malaria.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851646","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":"Designing Highly Potent Side-Chain Lactam-Bridged Cyclic Competence-Stimulating Peptide-Based Quorum-Sensing Modulators in <i>Streptococcus oligofermentans</i>.","authors":"Uttam Ghosh, Yftah Tal-Gan","doi":"10.1021/acsinfecdis.4c00773","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00773","url":null,"abstract":"<p><p><i>Streptococcus oligofermentans</i>, a Gram-positive bacterium found in the oral microbiome, shows promise as an oral probiotic for preventing dental caries. It exhibits a reverse correlation with <i>Streptococcus mutans</i>, a key caries-causing pathogen, likely due to its production of hydrogen peroxide, a process mediated by quorum sensing (QS). In this work, we set out to develop novel lactam-based cyclic analogues of the competence stimulating peptide (CSP) signal utilized by <i>S. oligofermentans</i> for QS activation. To this end, we first conducted a ring position scan, where we determined the best positions within the CSP sequence to use for macrolactamization. We then conducted systematic ring size and bridge position scans to fine-tune the cyclic peptide conformation and identified a cyclic analogue, CSP-cyc(K2E2), with enhanced biological activity, 7-fold more active than the native CSP signal. This analogue also exhibited improved stability toward enzymatic degradation, demonstrating this analogue's potential utility as a chemical probe to study interspecies interactions between oral microbes and as a potential therapeutic agent. Overall, our lead cyclic analogue could be applied to augment the biotherapeutic potential of <i>S. oligofermentans</i> against <i>S. mutans</i> infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833176","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":"Reductive Activation of Artefenomel (OZ439) by Fe(II)-Heme, Related to Its Antimalarial Activity.","authors":"Michel Nguyen, Lucie Paloque, Jeanne Manaranche, Mickaël Chabbert, Alexandre Hamouy, Marion Laurent, Jean-Michel Augereau, Catherine Claparols, Anne Robert, Françoise Benoit-Vical","doi":"10.1021/acsinfecdis.4c00787","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00787","url":null,"abstract":"<p><p>The 1,2,4-trioxolane antimalarial drug, OZ439 (artefenomel), exhibits cross-resistance to artemisinins <i>in vitro</i> with similar survival rates of artemisinin-resistant parasites after dihydroartemisinin or OZ439 exposure, suggesting that this drug shares some mechanisms of action with artemisinins. In this way, we investigated the <i>in vitro</i> reductive activation of OZ439 by heme in the presence of dithionite, demonstrating the formation of covalent heme-drug adducts. However, in the presence of the biologically abundant reductant glutathione instead of dithionite, heme-drug adducts were not detected, contrary to artemisinin that efficiently alkylates heme regardless of the reductant used. Conversely, the C-centered radical of OZ439 resulting from heme-mediated activation of the drug reacts with the thiol function of glutathione, thus confirming the ability of this drug to alkylate proteins or other biological targets. So, the difference in the mechanism of action between artemisinin and OZ439 <i>in vivo</i> may rely on the different proportions between heme alkylation and protein alkylation.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833180","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":"Efficacy and Possible Mechanism(s) of Action of Gallium Tetraphenylporphyrin Nanoparticles against HIV-TB Coinfection in an <i>In Vitro</i> Granuloma Structure Model.","authors":"Seoung-Ryoung Choi, Smita Kulkarni, Eusondia Arnett, Larry S Schlesinger, Bradley E Britigan, Prabagaran Narayanasamy","doi":"10.1021/acsinfecdis.4c00639","DOIUrl":"10.1021/acsinfecdis.4c00639","url":null,"abstract":"<p><p>Coinfection of <i>Mycobacterium tuberculosis</i> (Mtb) and human immunodeficiency virus-1 (HIV) is a significant public health concern. Treatment is challenging due to prolonged duration of therapy and drug interactions between antiretroviral therapy (ART) and anti-TB drugs. Noniron gallium <i>meso</i>-tetraphenyl porphyrin (GaTP), a heme mimetic, has shown broad antimicrobial activity. Here, we investigated the efficacy of nanoparticle encapsulating GaTP (GaNP) for the treatment of HIV and Mtb coinfection or single infection in <i>in vitro</i> granuloma structures. GaNP significantly reduced viable Mtb within primary human <i>in vitro</i> granuloma structures infected with Mtb H37Rv-lux and significantly reduced levels of HIV in CD4+ T cells infected with the virus axenically. Similarly, GaNP exhibited significant antimicrobial activity against HIV/Mtb-coinfected granuloma structures created <i>in vitro</i>, which contain the primary immune cells seen in human TB granulomas, including CD4+ T cells and macrophages, as assessed by a luciferase assay for Mtb and p24 ELISA for HIV detection. Furthermore, mechanistic studies revealed that GaTP increases the level of reactive oxygen species and inhibits catalase in Mtb. A significant increase in Mtb nitrate reductase activity was also observed when Mtb was incubated with GaTP and sodium nitrate. Overall, increased oxidative stress and nitrite levels induced by GaTP are consistent with the possibility that GaTP inhibits Mtb aerobic respiration, which leads to incomplete O₂ reduction and a shift to respiration using exogenous NO₃. These cumulative data continue to support the potential for developing the noniron heme analog GaTP and its nanoparticle GaNP as new therapeutic approaches for the treatment of HIV/Mtb coinfection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"4279-4290"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580917","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":"Eradication of <i>Pseudomonas aeruginosa</i> Persister Cells by Eravacycline.","authors":"Sweta Roy, Zeynep S Cakmak, Salma Mahmoud, Mahsa Sadeghzadeh, Guirong Wang, Dacheng Ren","doi":"10.1021/acsinfecdis.4c00349","DOIUrl":"10.1021/acsinfecdis.4c00349","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a leading bacterial pathogen that causes persistent infections. One major reason that antibiotics fail to clear such infections is the presence of a dormant subpopulation called persister cells. To eradicate persister cells, it is important to change drug development from traditional strategies that focus on growth inhibition to the search for new leads that can kill dormant cells. In this study, we demonstrate that eravacycline can effectively accumulate in <i>P. aeruginosa</i> persister cells, leading to strong killing during wakeup, including persister cells in both planktonic cultures and biofilms of the wild-type strain and its mucoid mutant. The effects of eravacycline on persister control were further validated <i>in vivo</i> using a lung infection model in mice. Collectively, these results demonstrate the possibility to control persister cells of bacterial pathogens by targeting dormancy.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"4127-4136"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612733","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":"Immunoproteomic and Immunoinformatic Approaches Identify Sensitive Antigens for Diagnosing <i>Anisakis pegreffii</i> Infection.","authors":"Xiaoxu Wang, Minhao Zeng, Guofeng Cheng","doi":"10.1021/acsinfecdis.4c00708","DOIUrl":"10.1021/acsinfecdis.4c00708","url":null,"abstract":"<p><p><i>Anisakis</i> are foodborne parasites that opportunistically parasitize humans, leading to acute abdominal symptoms and allergies. Besides gastroscopy, no other diagnostic technique is available. Consequently, it is necessary to identify specific biomarkers and then develop molecular techniques for diagnosing <i>Anisakis</i> infection. In the present study, we used immunoproteomic and immunoinformatic approaches to identify sensitive antigens for diagnosing <i>Anisakis pegreffii</i> infection. A total of three proteins, including Ani609 (VDK51609), Ani941 (VDK75941), and AniS13, were identified based on immunoinformatic results. Then, the indirect ELISA method was developed based on the recombinant proteins, showing a similar diagnostic capability to that of parasitic soluble proteins. Next, a <i>Gaussia</i> luciferase immunoprecipitation assay (LIPS) was further developed upon the fusion of the proteins and <i>Gaussia</i> luciferase. The LIPS method indicated that <i>A. pegreffii</i> infection could be detected in rats as early as 1 week post infection, especially for Ani941. Overall, we identified the novel antigens using immunoproteomic and immunoinformatic approaches and then developed a sensitive method for diagnosing <i>A. pegreffii</i> infection, particularly for the early stage.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"4360-4368"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566455","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":"Glycolipidomics of Liver Flukes and Host Tissues during Fascioliasis: Insights from Mass Spectrometry Imaging.","authors":"David Luh, Parviz Ghezellou, Sven Heiles, Svenja Gramberg, Simone Haeberlein, Bernhard Spengler","doi":"10.1021/acsinfecdis.4c00551","DOIUrl":"10.1021/acsinfecdis.4c00551","url":null,"abstract":"<p><p>Fascioliasis, a zoonotic disease caused by liver flukes of the genus <i>Fasciola</i>, poses significant health threats to both humans and livestock. While some infections remain asymptomatic, others can lead to fatal outcomes, particularly during the acute phase characterized by the migration of immature parasites causing severe liver damage. Through the combination of data acquired via high-spatial-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) and nanohydrophilic interaction chromatography tandem mass spectrometry, we investigated glycosphingolipids (GSLs) in both adult and immature parasite stages as well as the host liver and bile duct to unravel the intricacies of the host-pathogen interplay and associated pathology. Several GSLs showed characteristic distribution patterns within the parasite depending on the fatty acid composition of their ceramides, notably including GSLs carrying very long-chain fatty acids. Additionally, GSL compositions within the tegument of immature versus adult parasites varied, suggestive of tissue remodeling upon maturation. AP-SMALDI MSI further enabled the identification of GSLs potentially involved in <i>in vivo</i> interactions between the host and immature parasites. Moreover, our experiments unveiled alterations in other lipid classes during <i>Fasciola</i> infection, providing a broader understanding of lipidomic changes associated with the disease. Collectively, our findings contribute to a deeper comprehension of the molecular intricacies underlying fascioliasis, with a specific focus on GSLs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"4233-4245"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602187","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}