ACS Infectious Diseases最新文献

{"title":"Activity-Based Protein Profiling Identifies an α-Amylase Family Protein Contributing to the Virulence of Methicillin-Resistant <i>Staphylococcus aureus</i>.","authors":"Md Jalal Uddin, Kjersti Julin, Herman S Overkleeft, Mona Johannessen, Christian S Lentz","doi":"10.1021/acsinfecdis.4c00638","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00638","url":null,"abstract":"<p><p>In search of new putative antimicrobial drug targets in methicillin-resistant <i>Staphylococcus aureus</i>, we aimed to identify and characterize retaining glycosidase activities in this bacterial pathogen. Using activity-based protein profiling (ABPP), a panel of 7 fluorescent probes was screened to detect activities of diverse retaining glycosidase families. Based on this, a cocktail of 3 biotinylated probes (targeting α-glucosidases, β-galactosidases and α-fucosidases) was used for target enrichment and three glycoside hydrolase family proteins were identified by mass-spectrometry: 6-phospho-β-glucosidase (BglA), α-amylase family protein trehalase C (TreC), and autolysin (Atl). The physiological relevance of previously uncharacterized BglA and TreC was addressed in CRISPRi and inhibitor studies with the putative TreC inhibitor α-cyclophellitol-aziridine. Silencing of <i>tre</i>C did not affect bacterial growth in rich media, but reduced biofilm formation <i>in vitro</i>, and attenuated virulence during <i>Galleria mellonella</i> infection, warranting future investigations into the biochemical function of this enzyme.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363253","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":"Active- and Allosteric-Site Cyclic Peptide Inhibitors of Secreted <i>M. tuberculosis</i> Chorismate Mutase.","authors":"Renier H P van Neer, Patricia K Dranchak, Mahesh Aitha, Lijun Liu, Emma K Carlson, Isabella E Jacobsen, Kevin Battaile, Yuhong Fang, Dingyin Tao, Ganesha Rai, Janak Padia, Scott Lovell, Hiroaki Suga, James Inglese","doi":"10.1021/acsinfecdis.4c00798","DOIUrl":"10.1021/acsinfecdis.4c00798","url":null,"abstract":"<p><p>The secreted Chorismate mutase enzyme of <i>Mycobacterium tuberculosis</i> (*<i>Mtb</i>CM) is an underexplored potential target for the development of new antitubercular agents that are increasingly needed as antibiotic resistance rises in prevalence. As an enzyme suspected to be involved in virulence and host-pathogen interactions, disruption of its function could circumvent the difficulty of treating tuberculosis-infected granulomas. Drug development, however, is limited by novel ligand discovery. Currently, *<i>Mtb</i>CM activity is measured by using a low throughput acid/base-mediated product derivatization absorbance assay. Here, we utilized an RNA-display affinity selection approach enabled by the Random Peptides Integrated Discovery (RaPID) system to screen a vast library of macrocyclic peptides (MCP) for novel *<i>Mtb</i>CM ligands. Peptides identified from the RaPID selection, and analogs thereof identified by analyzing the selection population dynamics, produced a new class of *<i>Mtb</i>CM inhibiting MCPs. Among these were two noteworthy \"chorismides\", whose binding modes were elucidated by X-ray crystallography. Both were potent inhibitors of the CM enzyme activity. One was identified as an allosteric binding peptide revealing a novel inhibition approach, while the other is an active-site binding peptide that when conjugated to a fluorescent probe allowed for the development of a series of alternative fluorescence-based ligand-displacement assays that can be utilized for the assessment of potential *<i>Mtb</i>CM inhibitors.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187542","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":"Neutrophil-Leishmania infantum Interaction Induces Neutrophil Extracellular Traps, DAMPs, and Inflammatory Molecule Release","authors":"Paulo Ricardo Porfíriodo Nascimento*,&nbsp;Carolina Oliveira Mendes-Aguiar,&nbsp;Ingryd Câmara Morais,&nbsp;João Firmino Rodrigues Neto,&nbsp;Mary E. Wilson and Selma Maria Bezerra Jerônimo,&nbsp;","doi":"10.1021/acsinfecdis.4c0082010.1021/acsinfecdis.4c00820","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00820https://doi.org/10.1021/acsinfecdis.4c00820","url":null,"abstract":"<p >Neutrophils, the first cells to arrive at infection sites, release neutrophil extracellular traps (NETs) comprising nuclear and/or mitochondrial DNA webs decorated with proteins. Similar to other parasites, <i>Leishmania infantum</i> induces NET extrusion. However, our understanding of NET formation and neutrophil fate after NET release in a Leishmania infection context is limited. Our study aimed to determine the DNA origin of the NET scaffolds released by human neutrophils in response to chemical or <i>L. infantum</i> stimulation. Neutrophils were incubated with PMA, PHA, LPS, or <i>L. infantum</i>, followed by DNA and elastase activity quantification; additionally, we evaluated the source of DNA that composes NETs. Neutrophil viability was evaluated by annexin-V/7AAd labeling. Expression of IL6, TNFA, IL10, CXCL1, CXCL8, and FPR1 in response to the <i>L. infantum</i> interaction was assessed. Neutrophils incubated with chemicals or <i>L. infantum</i> released NETs. However, neutrophils stimulated by the chemicals showed lower viability after 1 h in comparison to neutrophils incubated with parasites. NETs from chemically stimulated neutrophils were mainly composed of nuclear DNA. Conversely, the NET induced by the parasites was of mitochondrial DNA origin and had no leishmanicidal activity. After 4 h of parasite stimulation, neutrophils peak the expression of genes such as IL6, TNFA, CXCL1, CXCL8, and FPR1. Our study demonstrates that neutrophils produce NETs after chemical or <i>L. infantum</i> exposure. Although they are not toxic to the parasite, NETs are released as danger signals. These findings support the role of neutrophils in releasing signaling molecules, which influence the inflammatory environment in which the infectious process occurs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"483–492 483–492"},"PeriodicalIF":4.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00820","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402328","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":"Ten Years of ACS Infectious Diseases – A Celebration of Excellence","authors":"Jayanta Haldar*,&nbsp;","doi":"10.1021/acsinfecdis.5c0005010.1021/acsinfecdis.5c00050","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00050https://doi.org/10.1021/acsinfecdis.5c00050","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"271–276 271–276"},"PeriodicalIF":4.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402218","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":"Infectious Diseases Chemical “Cookbooks”: Celebrating Women’s Authorship in ACS Infectious Diseases","authors":"Helen I. Zgurskaya*,&nbsp;","doi":"10.1021/acsinfecdis.4c0091610.1021/acsinfecdis.4c00916","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00916https://doi.org/10.1021/acsinfecdis.4c00916","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"264–270 264–270"},"PeriodicalIF":4.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402096","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":"Role of the Mobile Active Site Flap in IMP Dehydrogenase Inhibitor Binding","authors":"Xingyou Wang,&nbsp;Masha M. Rosenberg,&nbsp;Youngchang Kim,&nbsp;Natalia Maltseva,&nbsp;Gregory D. Cuny,&nbsp;Andrzej Joachimiak,&nbsp;Petr Kuzmič* and Lizbeth Hedstrom*,&nbsp;","doi":"10.1021/acsinfecdis.4c0063610.1021/acsinfecdis.4c00636","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00636https://doi.org/10.1021/acsinfecdis.4c00636","url":null,"abstract":"<p >Inosine 5′-monophosphate dehydrogenase (IMPDH) is a promising antibiotic target. This enzyme catalyzes the NAD-dependent oxidation of inosine 5′-monophosphate (IMP) to xanthosine 5′-monophosphate (XMP), which is the rate-limiting step in guanine nucleotide biosynthesis. Bacterial IMPDH-specific inhibitors have been developed that bind to the NAD⁺ site. These inhibitors display varied affinities to different bacterial IMPDHs that are not easily rationalized by X-ray crystal structures of enzyme–inhibitor complexes. Inspection of X-ray crystal structures of 25 enzyme–inhibitor complexes, including 10 newly described, suggested that a mobile active site flap may be a structural determinant of inhibitor potency. Saturation transfer difference NMR experiments also suggested that the flap may contact the inhibitors to varying extents in different IMPDHs. Flap residue Leu413 contacted some inhibitors but was not structured in the crystal structures of other inhibitor complexes. The substitution of Leu413 with Phe or Ala in <i>Bacillus anthracis</i> IMPDH had inhibitor-selective effects, suggesting residue 413 could be a structural determinant of affinity. Curiously, the Ala substitution increased the potency of most inhibitors, even those that contacted Leu413 in the crystal structures. Presteady-state and steady-state kinetics experiments showed that the Leu413Ala substitution had comparable effects on inhibitor binding to the noncovalent E·IMP complex and the covalent intermediate E-XMP*, suggesting that the flap had similar interactions in both complexes. These results demonstrate that contacts do not necessarily indicate favorable interactions, and poorly structured mobile regions should not be discounted when assessing binding determinants.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"442–452 442–452"},"PeriodicalIF":4.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402097","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":"Decoding the Role of Antimicrobial Peptides in the Fight against Mycobacterium tuberculosis","authors":"Sapna Saini,&nbsp;Sunny Pal and Rashmi Sharma*,&nbsp;","doi":"10.1021/acsinfecdis.4c0080610.1021/acsinfecdis.4c00806","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00806https://doi.org/10.1021/acsinfecdis.4c00806","url":null,"abstract":"<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":"11 2","pages":"350–365 350–365"},"PeriodicalIF":4.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402409","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 Plasmodium","authors":"Arpitha Suryavanshi,&nbsp;Anusha Chandrashekarmath,&nbsp;Nivedita Pandey and Hemalatha Balaram*,&nbsp;","doi":"10.1021/acsinfecdis.4c0078810.1021/acsinfecdis.4c00788","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00788https://doi.org/10.1021/acsinfecdis.4c00788","url":null,"abstract":"<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":"11 2","pages":"335–349 335–349"},"PeriodicalIF":4.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402233","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 Pseudomonas aeruginosa PAO1","authors":"Paul J. Hensbergen*,&nbsp;Loes van Huijkelom,&nbsp;Jordy van Angeren,&nbsp;Arnoud H. de Ru,&nbsp;Bart Claushuis,&nbsp;Peter A. van Veelen,&nbsp;Wiep Klaas Smits and Jeroen Corver,&nbsp;","doi":"10.1021/acsinfecdis.4c0089610.1021/acsinfecdis.4c00896","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00896https://doi.org/10.1021/acsinfecdis.4c00896","url":null,"abstract":"<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":"11 2","pages":"518–528 518–528"},"PeriodicalIF":4.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00896","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402200","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":"Advantages and Challenges of Using Antimicrobial Peptides in Synergism with Antibiotics for Treating Multidrug-Resistant Bacteria","authors":"Regina Meneses Gonçalves,&nbsp;Bruna Estéfani Dutra Monges,&nbsp;Karen Garcia Nogueira Oshiro,&nbsp;Elizabete de Souza Cândido,&nbsp;João Pedro Farias Pimentel,&nbsp;Octávio Luiz Franco and Marlon Henrique Cardoso*,&nbsp;","doi":"10.1021/acsinfecdis.4c0070210.1021/acsinfecdis.4c00702","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00702https://doi.org/10.1021/acsinfecdis.4c00702","url":null,"abstract":"<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":"11 2","pages":"323–334 323–334"},"PeriodicalIF":4.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00702","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402209","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}