ACS Infectious Diseases最新文献

{"title":"The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against <i>Plasmodium falciparum</i>.","authors":"Savannah J Watson, Mariëtte E van der Watt, Anjo Theron, Janette Reader, Sizwe Tshabalala, Erica Erlank, Lizette L Koekemoer, Mariska Naude, Marianna Stampolaki, Feyisola Adewole, Katie Sadowska, Pilar Pérez-Lozano, Andreea L Turcu, Santiago Vázquez, Jihee Ko, Ben Mazurek, Davinder Singh, Satish R Malwal, Mathew Njoroge, Kelly Chibale, Oluseye K Onajole, Antonios Kolocouris, Eric Oldfield, Lyn-Marié Birkholtz","doi":"10.1021/acsinfecdis.4c00461","DOIUrl":"10.1021/acsinfecdis.4c00461","url":null,"abstract":"<p><p>Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite <i>Plasmodium falciparum</i> pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC₅₀) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3358-3367"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981103","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":"Efficient and Selective, In Vitro and In Vivo, Antimicrobial Photodynamic Therapy with a Dicationic Chlorin in Combination with KI.","authors":"Anita S Amorim, Zoe A Arnaut, Ana I Mata, Barbara Pucelik, Agata Barzowska, Gabriela J da Silva, Mariette M Pereira, Janusz M Dąbrowski, Luis G Arnaut","doi":"10.1021/acsinfecdis.4c00492","DOIUrl":"10.1021/acsinfecdis.4c00492","url":null,"abstract":"<p><p>Various cationic photosensitizers employed in antimicrobial photodynamic therapy (aPDT) have the ability to photoinactivate planktonic bacteria under conditions of low phototoxicity to mammalian cells and without generating antimicrobial resistance (AMR). However, the photoinactivation of biofilms requires orders-of-magnitude higher photosensitizer concentrations, which become toxic to host cells. Remarkably, the bactericidal effect of a dicationic di-imidazolyl chlorin toward planktonic <i>S. aureus</i> and <i>E. coli</i> was observed in this work for concentrations below 400 nM under illumination at 660 nm and below 50 μM for the corresponding biofilms. At the latter concentrations, the chlorin is phototoxic toward human keratinocyte cells. However, in the presence of 50 mM KI, bactericidal concentrations are reduced to less than 50 nM for planktonic bacteria and to less than 1 μM for biofilms. It is shown that the potentiation with KI involves the triiodide anion. This potentiation elicits a bactericidal effect without appreciable cytotoxicity to keratinocytes. It becomes possible to selectively inactivate biofilms with aPDT. An exploratory study treating mice with wounds infected with <i>E. coli</i> expressing GFP with 20 μM chlorin and 120 J cm^-2 at 652 nm confirmed the potential of this chlorin to control localized infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3368-3377"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992177","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":"Growth Phase Contribution in Dictating Drug Transport and Subcellular Accumulation inside <i>Escherichia coli</i>.","authors":"Deepak Kumar, Anindita Gayen, Manabendra Chandra","doi":"10.1021/acsinfecdis.4c00252","DOIUrl":"10.1021/acsinfecdis.4c00252","url":null,"abstract":"<p><p>Depending upon nutrient availability, bacteria transit to multiple growth phases. The transition from the active to nongrowing phase results in reduced drug efficacy and, in some cases, even multidrug resistance. However, due to multiple alterations in the cell envelope, probing the drug permeation kinetics during growth phases becomes perplexing, especially across the Gram-negative bacteria's complex dual membrane envelope. To advance the understanding of drug permeation during the life cycle of Gram-negative bacteria, we sought to address two underlying objectives: (a) how changes are occurring inside the bacterial envelope during growth and (b) how the drug permeation and accumulation vary across both the membranes and in subcellular compartments during growth. Both objectives are met with the help of nonlinear optical technique second-harmonic generation spectroscopy (SHG). Specifically, using SHG, we probed the transport kinetics and accumulation of a quaternary ammonium compound (QAC), malachite green, inside <i>Escherichia coli</i> in various growth phases. Further insight about another QAC molecule, propidium iodide, is accomplished using fluorescence microscopy. Results indicate that actively growing cells have faster drug transport and higher cytoplasmic accumulation than slow- or nongrowing cells. In this regard, the <i>rpoS</i> gene plays a crucial role in limiting drug transport across the saturation phase cultures. Moreover, within a particular growth phase, membrane permeability undergoes gradual changes much before the subsequent growth phase commences. These outcomes signify the importance of reporting the growth phase and rate in drug efficacy studies.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"3233-3244"},"PeriodicalIF":4.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043775","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":"Fatty Acid Uptake in Klebsiella pneumoniae and the Landscape of Its Infectious Niches","authors":"Ella Haracic, Jack K. Waters, To Nguyen Thi Nguyen, Xenia Kostoulias, Brynley J. Davies, Long Yu, Anton Y. Peleg, Vincent Bulone, Francesca L. Short, Bart A. Eijkelkamp","doi":"10.1021/acsinfecdis.4c00307","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00307","url":null,"abstract":"<i>Klebsiella pneumoniae</i> is consistently ranked among the most problematic multidrug-resistant bacterial pathogens in healthcare systems. Developing novel treatments requires a better understanding of its interaction with the host environment. Although bacteria can synthesize fatty acids, emerging findings suggest a potential preference for their acquisition from the host. Fatty acid profiling of mice revealed a dramatic increase in the level of hepatic lipids during <i>K</i>. <i>pneumoniae</i> infection. The <i>K</i>. <i>pneumoniae</i> fatty acid composition and uptake capabilities were found to be largely clonally conserved. Correlations between fatty acid uptake, outer membrane vesicle production, and cell permeability were observed, but this did not translate to alterations in cell morphology, capsule production, or antimicrobial susceptibility. Importantly, hyper-capsulation did not prevent the uptake of hydrophobic fatty acids. The uptake of a saturated fatty acid by hypervirulent <i>K</i>. <i>pneumoniae</i> isolate may provide insights into the clinical association of <i>K</i>. <i>pneumoniae</i> infections with hyperlipidemic and/or obese individuals.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227439","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":"The Road Ahead: Advancing Antifungal Vaccines and Addressing Fungal Infections in the Post-COVID World","authors":"Xiaolong Gong, Mohmmad Younus Wani, Abdullah Saad Al-Bogami, Aijaz Ahmad, Keven Robinson, Amber Khan","doi":"10.1021/acsinfecdis.4c00245","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00245","url":null,"abstract":"In impoverished nations, the COVID-19 pandemic has led to a widespread occurrence of deadly fungal diseases like mucormycosis. The limited availability of effective antifungal treatments and the emergence of drug-resistant fungal strains further exacerbate the situation. Factors such as systemic steroid use, intravenous drug misuse, and overutilization of broad-spectrum antimicrobials contribute to the prevalence of hospital-acquired infections caused by drug-resistant fungi. Fungal infections exploit compromised immune status and employ intricate mechanisms to evade immune surveillance. The immune response involves the innate and adaptive immune systems, leading to phagocytic and complement-mediated elimination of fungi. However, resistance to antifungals poses a challenge, highlighting the importance of antifungal prophylaxis and therapeutic vaccination. Understanding the host-fungal immunological interactions and developing vaccines are vital in combating fungal infections. Further research is needed to address the high mortality and morbidity associated with multidrug-resistant fungal pathogens and to develop innovative treatment drugs and vaccines. This review focuses on the global epidemiological burden of fungal infections, host-fungal immunological interactions, recent advancements in vaccine development and the road ahead.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"59 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219655","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":"Crystal Structures of the Acinetobacter baumannii Macrolide Phosphotransferase E","authors":"Qianqian Qi, Linghan Kuang, Jing Liao, Xiang Wang, Yanxia Zhou, Li Guo, Yongmei Jiang","doi":"10.1021/acsinfecdis.4c00300","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00300","url":null,"abstract":"<i>Acinetobacter baumannii</i> (<i>A. baumannii</i>) challenges clinical infection treatment due to its resistance to various antibiotics. Multiple resistance genes in the core genome or mobile elements contribute to multidrug resistance in <i>A. baumannii</i>. Macrolide phosphotransferase gene <i>mphE</i> has been identified in <i>A. baumannii</i>, which is particularly relevant to macrolide antibiotics. Here, we determined the structure of MphE protein in three states: the apo state, the complex state with erythromycin and guanosine triphosphate (GTP), and the complex state with azithromycin and guanosine. Interestingly, GTP and two magnesium ions were observed in the erythromycin-bound MphE complex. This structure captured the active state of MphE, in which the magnesium ions stabilized the active site and assisted the transfer of phosphoryl groups. Based on these structures, we verified that the conserved residues Asp29, Asp194, His199, and Asp213 play an important role in the catalytic phosphorylation of MphE leading to drug resistance. Our work helps to understand the molecular basis of drug resistance and provides reference targets for optimizing macrolide antibiotics.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219424","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":"ErpY-like Protein Interaction with Host Thrombin and Fibrinogen Intervenes the Plasma Coagulation through Extrinsic and Intrinsic Pathways","authors":"Saswat Hota,&nbsp; and ,&nbsp;Manish Kumar*,&nbsp;","doi":"10.1021/acsinfecdis.4c0026610.1021/acsinfecdis.4c00266","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00266https://doi.org/10.1021/acsinfecdis.4c00266","url":null,"abstract":"<p >The survival and proliferation of pathogenic <i>Leptospira</i> within a host are complex phenomena that require careful consideration. The ErpY-like lipoprotein, found on the outer membrane surface of <i>Leptospira</i>, plays a crucial role in enhancing the bacterium’s pathogenicity. The rErpY-like protein, in its recombinant form, contributes significantly to spirochete virulence by interacting with various host factors, including host complement regulators. This interaction facilitates the bacterium’s evasion of the host complement system, thereby augmenting its overall pathogenicity. The rErpY-like protein exhibits a robust binding affinity to soluble fibrinogen, a vital component of the host coagulation system. In this study, we demonstrate that the rErpY-like protein intervenes in the clotting process of the platelet-poor citrated plasma of bovines and humans in a concentration-dependent manner. It significantly reduces clot density, alters the viscoelastic properties of the clot, and diminishes the average clotting rate in plasma. Furthermore, the ErpY-like protein inhibits thrombin-catalyzed fibrin formation in a dose-dependent manner and exhibits saturable binding to thrombin, suggesting its significant role in leptospiral infection. These findings provide compelling evidence for the anticoagulant effect of the ErpY-like lipoprotein and its significant role in leptospiral infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"10 9","pages":"3256–3272 3256–3272"},"PeriodicalIF":4.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228171","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":"STING Agonist Induced Innate Immune Responses Drive Anti-Respiratory Virus Activity In Vitro with Limited Antiviral Efficacy In Vivo","authors":"Rebecca Broeckel*,&nbsp;Amanda Browne,&nbsp;Scott Sucoloski,&nbsp;Juan Cantizani,&nbsp;Juliet. K. Simpson,&nbsp;Scott Pesiridis,&nbsp;Joshi M. Ramanjulu,&nbsp;Neil Stokes and Priya Luthra*,&nbsp;","doi":"10.1021/acsinfecdis.4c0050410.1021/acsinfecdis.4c00504","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00504https://doi.org/10.1021/acsinfecdis.4c00504","url":null,"abstract":"<p >The emergence of SARS-CoV-2 and seasonal outbreaks of other respiratory viruses highlight the urgent need for broad-spectrum antivirals to treat respiratory tract infections. Stimulator of interferon genes (STING) is a key component of innate immune signaling and plays a critical role in protection of the host against viral infections. Previously the STING agonist diABZI-4, a diamidobenzimidazole-based compound, demonstrated protection against SARS-CoV-2 both <i>in vitro</i> and <i>in vivo</i>. However, its broad-spectrum antiviral activity against other respiratory viruses in human airway epithelial cells, which are the primary targets of these infections, is not well established. In this study, we demonstrated that diABZI-4 stimulated robust innate immune responses protecting lung cells against a wide range of respiratory viruses, including influenza A virus (IAV), common cold coronaviruses, SARS-CoV-2, human rhinovirus (HRV), and human parainfluenza virus. diABZI-4 was highly active in physiologically relevant human airway epithelial tissues grown at the air–liquid interface, blocking replication of IAV, SARS-CoV-2, and HRV in these tissues. Furthermore, treatment of macrophages with diABZI-4 resulted in the secretion of cytokines that protected the primary airway epithelial cells from IAV infection. Despite the promising <i>in vitro</i> pan-antiviral activity, intranasal administration of diABZI-4 in mice provided early, but not sustained, inhibition of IAV replication in the lungs. These data highlight the complexities of the relationship between timing of STING agonist-driven inflammatory responses and viral replication dynamics, emphasizing the development challenge posed by STING agonists as potential therapeutics against respiratory viruses.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"10 9","pages":"3392–3407 3392–3407"},"PeriodicalIF":4.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228009","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":"Intranasal Self-Adjuvanted Lipopeptide Vaccines Elicit High Antibody Titers and Strong Cellular Responses against SARS-CoV-2","authors":"Joshua W. C. Maxwell,&nbsp;Skye Stockdale,&nbsp;Erica L. Stewart,&nbsp;Caroline L. Ashley,&nbsp;Lachlan J. Smith,&nbsp;Megan Steain,&nbsp;James A. Triccas,&nbsp;Scott N. Byrne,&nbsp;Warwick J. Britton,&nbsp;Anneliese S. Ashhurst* and Richard J. Payne*,&nbsp;","doi":"10.1021/acsinfecdis.4c0054410.1021/acsinfecdis.4c00544","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00544https://doi.org/10.1021/acsinfecdis.4c00544","url":null,"abstract":"<p >Despite concerted efforts to tackle the COVID-19 pandemic, the persistent transmission of SARS-CoV-2 demands continued research into novel vaccination strategies to combat the virus. In light of this, intranasally administered peptide vaccines, particularly those conjugated to an immune adjuvant to afford so-called “self-adjuvanted vaccines”, remain underexplored. Here, we describe the synthesis and immunological evaluation of self-adjuvanting peptide vaccines derived from epitopes of the spike glycoprotein of SARS-CoV-2 covalently fused to the potent adjuvant, Pam₂Cys, that targets toll-like receptor 2 (TLR2). When administered intranasally, these vaccines elicited a strong antigen-specific CD4⁺ and CD8⁺ T-cell response in the lungs as well as high titers of IgG and IgA specific to the native spike protein of SARS-CoV-2. Unfortunately, serum and lung fluid from mice immunized with these vaccines failed to inhibit viral entry in spike-expressing pseudovirus assays. Following this, we designed and synthesized fusion vaccines composed of the T-cell epitope discovered in this work, covalently fused to epitopes of the receptor-binding domain of the spike protein reported to be neutralizing. While antibodies elicited against these fusion vaccines were not neutralizing, the T-cell epitope retained its ability to stimulate strong antigen-specific CD4⁺ lymphocyte responses within the lungs. Given the Spike_(883–909) region is still completely conserved in SARS-CoV-2 variants of concern and variants of interest, we envision the self-adjuvanting vaccine platform reported here may inform future vaccine efforts.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"10 9","pages":"3419–3429 3419–3429"},"PeriodicalIF":4.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228447","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 and Biosynthesis of Persiathiacins: Unusual Polyglycosylated Thiopeptides Active Against Multidrug Resistant Tuberculosis","authors":"Yousef Dashti*,&nbsp;Fatemeh Mohammadipanah,&nbsp;Yu Zhang,&nbsp;Pietra M. Cerqueira Diaz,&nbsp;Anthony Vocat,&nbsp;Daniel Zabala,&nbsp;Christopher D. Fage,&nbsp;Isolda Romero-Canelon,&nbsp;Boyke Bunk,&nbsp;Cathrin Spröer,&nbsp;Lona M. Alkhalaf,&nbsp;Jörg Overmann,&nbsp;Stewart T. Cole and Gregory L. Challis*,&nbsp;","doi":"10.1021/acsinfecdis.4c0050210.1021/acsinfecdis.4c00502","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00502https://doi.org/10.1021/acsinfecdis.4c00502","url":null,"abstract":"<p >Thiopeptides are ribosomally biosynthesized and post-translationally modified peptides (RiPPs) that potently inhibit the growth of Gram-positive bacteria by targeting multiple steps in protein biosynthesis. The poor pharmacological properties of thiopeptides, particularly their low aqueous solubility, has hindered their development into clinically useful antibiotics. Antimicrobial activity screens of a library of Actinomycetota extracts led to discovery of the novel polyglycosylated thiopeptides persiathiacins A and B from <i>Actinokineospora</i> sp. UTMC 2448. Persiathiacin A is active against methicillin-resistant <i>Staphylococcus aureus</i> and several <i>Mycobacterium tuberculosis</i> strains, including drug-resistant and multidrug-resistant clinical isolates, and does not significantly affect the growth of ovarian cancer cells at concentrations up to 400 μM. Polyglycosylated thiopeptides are extremely rare and nothing is known about their biosynthesis. Sequencing and analysis of the <i>Actinokineospora</i> sp. UTMC 2448 genome enabled identification of the putative persiathiacin biosynthetic gene cluster (BGC). A cytochrome P450 encoded by this gene cluster catalyzes the hydroxylation of nosiheptide in vitro and in vivo, consistent with the proposal that the cluster directs persiathiacin biosynthesis. Several genes in the cluster encode homologues of enzymes known to catalyze the assembly and attachment of deoxysugars during the biosynthesis of other classes of glycosylated natural products. One of these encodes a glycosyl transferase that was shown to catalyze attachment of a <span>D</span>-glucose residue to nosiheptide in vitro. The discovery of the persiathiacins and their BGC thus provides the basis for the development of biosynthetic engineering approaches to the creation of novel (poly)glycosylated thiopeptide derivatives with enhanced pharmacological properties.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"10 9","pages":"3378–3391 3378–3391"},"PeriodicalIF":4.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228268","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}