ACS Infectious Diseases最新文献

Functionalized Phenyl Peptoids with Enhanced Antibacterial Potency. 具有增强抗菌效力的功能化苯基肽。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-30 DOI: 10.1021/acsinfecdis.5c00148

Ghayah Bahatheg, Rajesh Kuppusamy, Muhammad Yasir, Shyam Kumar Mishra, David StClair Black, Mark Willcox, Naresh Kumar

{"title":"Functionalized Phenyl Peptoids with Enhanced Antibacterial Potency.","authors":"Ghayah Bahatheg, Rajesh Kuppusamy, Muhammad Yasir, Shyam Kumar Mishra, David StClair Black, Mark Willcox, Naresh Kumar","doi":"10.1021/acsinfecdis.5c00148","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00148","url":null,"abstract":"Antimicrobial resistance (AMR) to traditional antibiotics and natural peptides has been recognized as a global challenge requiring efforts to address its widespread impact. Peptoids represent a promising class of peptidomimetics with proven activity against multidrug-resistant bacteria and show less susceptibility to enzymatic degradation. In this study, building on our previous design of dimeric peptoids, 22 amino and guanidino compounds of functionalized phenyl-dimeric peptoids were synthesized, incorporating electron-withdrawing and donating substituents, as well as the parent peptoid without substituents. The electronic nature of the substituent and the guanidino group played a vital role in tuning the peptoid antibacterial activity. Guanidino peptoids 11h, 11i, and 11f were the most effective peptoids against Gram-positive and Gram-negative bacteria, with MICs of 0.75 to 2.6 μg mL-1 against Staphylococcus aureus strains and MICs of 6 to 10.9 μg mL-1 against Escherichia coli. Guanidino peptoids in the presence of the electron-withdrawing group, including halogens and a nitro group, or in the presence of moderate electron-donating groups such as methyl and tert-butyl, showed the best activity against bacteria, especially Gram-positive strains. Mechanistic studies using cytoplasmic membrane permeability and flow cytometric viability measurements revealed that the antibacterial effect might be mostly attributed to bacterial cell membrane damage. These promising antibacterial peptoids exhibited negligible hemolysis of mammalian red blood cells. Peptoid 11f, containing a methyl group, was the most effective disruptor and inhibitor of S. aureus or E. coli biofilms. These peptoids have the potential to be used as antibacterial surface coatings or therapeutic antibacterial agents.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186064","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}

引用次数: 0

Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease. P2基团的空间和电子性质对共价抑制剂与SARS-CoV-2主蛋白酶结合的影响。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-29 DOI: 10.1021/acsinfecdis.5c00246

Dipendra Bhandari, Leighton Coates, Annie Aniana, John M Louis, Peter V Bonnesen, Andrey Kovalevsky

{"title":"Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease.","authors":"Dipendra Bhandari, Leighton Coates, Annie Aniana, John M Louis, Peter V Bonnesen, Andrey Kovalevsky","doi":"10.1021/acsinfecdis.5c00246","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00246","url":null,"abstract":"The main protease (MPro) of SARS-CoV-2 is a critical enzyme required for viral replication, making it a prime target for antiviral drug development. Covalent inhibitors, which form a stable interaction with the catalytic C145, have demonstrated strong inhibition of MPro, but the influence of steric and electronic properties of P2 substituents, designed to engage the S2 substrate-binding subsite within the MPro active site, on inhibitor binding affinity remains underexplored. In this study, we design and characterize two hybrid covalent inhibitors, BBH-3 and BBH-4, and present their X-ray crystallographic structures in complex with MPro, providing molecular insights into how their distinct P2 groups, a dichlorobenzyl moiety in BBH-3 and an adamantyl substituent in BBH-4, affect binding conformation and active site adaptability. Comparative structural analyses with previously characterized inhibitors, including BBH-2 and Mcule-5948770040, reveal how the P2 bulkiness and electronic properties influence active site dynamics, particularly through interactions with the S2 and S5 subsites. The P2 group of BBH-3 induces conformational shifts in the S2 helix and the S5 loop, while BBH-4 displaces M49, stabilizing its binding through hydrophobic interactions. Isothermal titration calorimetry further elucidates the impact of P2 modifications on inhibitor affinity, revealing a delicate balance between enthalpic and entropic contributions. The data demonstrate that BBH-3 exhibits less favorable binding, affirming that dichlorobenzyl substitution at the P2 position has a more negative impact on the affinity for MPro than bulky saturated cyclic groups. This underscores the feature that MPro active site malleability may be accompanied by a conformational strain.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172076","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}

引用次数: 0

Mapping of Mycobacterial Enzymes Involved in Triacylglycerol Accumulation as Intrabacterial Lipid Inclusions Using Activity-Based Multitarget Inhibitor Probes. 利用基于活性的多靶点抑制剂探针定位参与三酰基甘油积聚的分枝杆菌酶作为细菌内脂质包裹体。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-29 DOI: 10.1021/acsinfecdis.5c00127

Romain Avellan, Jordan Lehoux, Thomas Francis, Tonia Dargham, Léa Celik, Alexandre Guy, Isabelle Poncin, Vanessa Point, Laurent Kremer, Thierry Durand, Stéphane Audebert, Luc Camoin, Christopher Spilling, Pierre Santucci, Céline Crauste, Stéphane Canaan, Jean-François Cavalier

{"title":"Mapping of Mycobacterial Enzymes Involved in Triacylglycerol Accumulation as Intrabacterial Lipid Inclusions Using Activity-Based Multitarget Inhibitor Probes.","authors":"Romain Avellan, Jordan Lehoux, Thomas Francis, Tonia Dargham, Léa Celik, Alexandre Guy, Isabelle Poncin, Vanessa Point, Laurent Kremer, Thierry Durand, Stéphane Audebert, Luc Camoin, Christopher Spilling, Pierre Santucci, Céline Crauste, Stéphane Canaan, Jean-François Cavalier","doi":"10.1021/acsinfecdis.5c00127","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00127","url":null,"abstract":"Lipids play a critical role in the physiology, life cycle, and pathogenicity of mycobacteria. They largely participate in host-pathogen interactions and fulfill important functions ranging from cell wall biosynthesis/maintenance, bacterial growth dynamics, and long-term persistence. In that context, triacylglycerol, a specific subtype of neutral lipid, is stored as intrabacterial lipid inclusions (ILI), which have been described as important structures for long-term survival and persistence within the host. However, the enzymes involved in ILI formation and degradation remain largely undefined. Using bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) of newly synthesized oxadiazolone (OX), cyclophostin, and cyclipostins (CyC) probes, we report the direct capture of target proteins in Mycobacterium abscessus growing under carbon excess and nitrogen-deprived in vitro conditions that promote triacylglycerol production and ILI formation. This approach led to the identification of a set of 65 enzymes potentially involved in global processes related to ILI anabolism. Among these, the long-chain-fatty-acid--CoA ligase MAB_1978c/FadD15 has been validated as a pivotal enzyme that colocalizes on ILI and as a major contributor in ILI formation in M. abscessus.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172078","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}

引用次数: 0

Development of a Universal Type A Influenza Viral RdRp-Induced Reporter System with Potential for Antiviral Drug Screening. 一种具有抗病毒药物筛选潜力的通用型a型流感病毒rdrp诱导报告系统的建立

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-27 DOI: 10.1021/acsinfecdis.4c00892

Yuehong Chen, Wenguang Yang, Liangning Liao, Jing Li, Sen Zhang, Xiaoping Kang, Yuchang Li, Lu Zhao, Bao Dong, Huiyao Wang, Yi Hu, Ye Feng, Tao Jiang

{"title":"Development of a Universal Type A Influenza Viral RdRp-Induced Reporter System with Potential for Antiviral Drug Screening.","authors":"Yuehong Chen, Wenguang Yang, Liangning Liao, Jing Li, Sen Zhang, Xiaoping Kang, Yuchang Li, Lu Zhao, Bao Dong, Huiyao Wang, Yi Hu, Ye Feng, Tao Jiang","doi":"10.1021/acsinfecdis.4c00892","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00892","url":null,"abstract":"The reemergence of new influenza strains and the rise of drug-resistant variants highlighted the urgent need for continuous development of novel antiviral therapies. Previously, reporter virus-based assays were commonly used for the screening of anti-influenza drugs. However, developing reporter viruses tailored to various influenza strains proved to be a time-consuming and labor-intensive process. In this study, we developed a universal MDCK cell-based reporter system that used viral RdRp activity to assess the efficacy of antiviral drugs against live influenza virus. This system employed Gaussia luciferase (Gluc) expression, driven by an RNA polymerase II (Pol-II) promoter and influenza virus RNA promoters recognized by polymerases from different influenza A virus (IAV) subtypes, facilitating transcription and translation of Gluc. The direct correlation between Gluc activity and viral RNA replication was confirmed. The drug evaluation results demonstrated a positive correlation between Gluc expression and the inhibitory effects of RdRp inhibitors when assessed with H1N1, H3N2, and H9N2 viruses. The study established a sensitive and rapid assay for researching and developing drugs targeting influenza RdRp without modifying the viruses, which will accelerate the development of next-generation antivirals and facilitate rapid testing of emerging influenza variants.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148660","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}

引用次数: 0

Design of Epitopes from Treponema pallidum Lipoprotein Antigens for Syphilis Diagnosis and Treatment Prognosis. 梅毒螺旋体脂蛋白抗原表位设计对梅毒诊断和治疗预后的影响。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-23 DOI: 10.1021/acsinfecdis.5c00155

Letícia Alves Borghezan, Lara Cândida de Sousa Machado, Iara Barreto Neves Oliveira, Mírian Ívens Fagundes, Nicoly Silveira Apolidório, Renato Canevari Dutra da Silva, Victor Garcia Freire, Antonio Augusto Schafer, Rahisa Scussel, Ricardo Andrez Machado-de-Ávila

{"title":"Design of Epitopes from Treponema pallidum Lipoprotein Antigens for Syphilis Diagnosis and Treatment Prognosis.","authors":"Letícia Alves Borghezan, Lara Cândida de Sousa Machado, Iara Barreto Neves Oliveira, Mírian Ívens Fagundes, Nicoly Silveira Apolidório, Renato Canevari Dutra da Silva, Victor Garcia Freire, Antonio Augusto Schafer, Rahisa Scussel, Ricardo Andrez Machado-de-Ávila","doi":"10.1021/acsinfecdis.5c00155","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00155","url":null,"abstract":"Syphilis, a multistage sexually transmitted infection, causes severe complications if untreated. Accurate diagnosis remains difficult due to the low protein content of Treponema pallidum and in vitro culture difficulty. Advances in immunoproteomics have identified key antigens that enhance diagnostic accuracy. Epitopes of immunodominant antigen proteins Tp0171, Tp0435, Tp0574, Tp0684, and Tp0453 were designed by bioinformatics tools, and mimetic peptides were chemically synthesized. A diagnostic accuracy cross-sectional study was performed to validate a prototype technology as a serodiagnosis platform for syphilis. Five peptides were used as antigens in a peptide-based ELISA against serum samples from syphilis-positive or noninfected patients (n = 122). CETp0435 achieved 100% sensitivity and specificity with a high accuracy. The peptides CETp0171 and CETp0574 demonstrated high diagnostic performance, with sensitivity above 83% and specificity >90%. Peptides CETp0684 and CETp0453 exhibited sensitivity above 80% and 90%, respectively; CETp0453 showed reduced specificity (∼66%). The peptides CETp0435 and CETp0171 maintained high diagnostic accuracy across syphilis stages, with a sensitivity above 83% and a specificity exceeding 97%. Peptides CETp0435 and CETp0171 effectively monitored syphilis treatment, as evidenced by the significant post-treatment decline in serum antibody levels, supporting their potential for evaluating the therapeutic efficacy. We obtained two epitopes mimetic peptides as advantageous antigens for serodiagnosis and treatment monitoring.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126216","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}

引用次数: 0

Bumped Kinase Inhibitors Inhibit both Toxoplasma gondii MAPKL1 and CDPK1. 撞击激酶抑制剂抑制弓形虫MAPKL1和CDPK1。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-23 DOI: 10.1021/acsinfecdis.5c00051

Jemma A Montgomery, P Holland Alday, Ryan Choi, Monique Khim, Bart L Staker, Matthew A Hulverson, Kayode K Ojo, Erkang Fan, Wesley C Van Voorhis, J Stone Doggett

{"title":"Bumped Kinase Inhibitors Inhibit both Toxoplasma gondii MAPKL1 and CDPK1.","authors":"Jemma A Montgomery, P Holland Alday, Ryan Choi, Monique Khim, Bart L Staker, Matthew A Hulverson, Kayode K Ojo, Erkang Fan, Wesley C Van Voorhis, J Stone Doggett","doi":"10.1021/acsinfecdis.5c00051","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00051","url":null,"abstract":"A subset of bumped kinase inhibitors (BKIs) has been optimized to inhibit the calcium dependent protein kinase 1 (TgCDPK1; TGGT1_301440) of Toxoplasma gondii and pathogenic Cryptosporidium species. Extensive preclinical development of BKIs has identified BKI-1748 as a highly effective lead compound for toxoplasmosis. Phenotypic and therapeutic effects of BKIs have suggested that BKIs may have targets other than TgCDPK1. The mechanism of BKI-1748 action was further investigated using a forward genetic screen of chemical mutagenesis, selection of BKI-1748 resistant clones, and whole genome sequence analysis. Resistant clones were found to have single nucleotide changes in the ATP binding site of the T. gondii mitogen-activated protein kinase-like 1 gene (TgMAPKL1; TGGT1_312570). One of the mutations found in the ATP binding pocket, Leu162Gln, was introduced into a wild-type strain, resulting in 2 to 6-fold resistance to BKI-1748 and a set of structurally varied BKIs. A strain with a TgCDPK1 gatekeeper substitution, Gly128Met, was also created and demonstrated a similar degree of resistance. The combination of TgMAPKL1 and TgCDPK1 substitutions together in a single strain resulted in a substantial increase in resistance to BKIs, up to 157-fold. The identification of TgMAPKL1 in addition to TgCDPK1 as a target of BKIs provides a greater understanding of the BKI mechanism of action that is important for further therapeutic development and suggests a high genetic barrier to meaningful drug resistance for this promising class of compounds.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126215","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}

引用次数: 0

SerpinB3/Protease Activated Receptor-2 Axis Is Essential for SARS CoV-2 Infection. SerpinB3/蛋白酶激活受体-2轴对SARS CoV-2感染至关重要

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-23 DOI: 10.1021/acsinfecdis.5c00145

Ilaria Frasson, Santina Quarta, Mariagrazia Ruvoletto, Alessandra Biasiolo, Monica Chinellato, Cristian Turato, Maristella Maggi, Laura Cendron, Sara N Richter, Patrizia Pontisso

引用次数: 0

Antiviral Activity of the Acyclic Nucleoside Phosphonate Prodrug LAVR-289 against Poxviruses and African Swine Fever Virus. 磷酸无环核苷前药LAVR-289对痘病毒和非洲猪瘟病毒的抗病毒活性研究

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-22 DOI: 10.1021/acsinfecdis.5c00169

Elie Marcheteau, Estelle Mosca, Gaelle Frenois-Veyrat, Sandrine Kappler-Gratias, Laetitia Boutin, Sokunthea Top, Thomas Mathieu, Cyril Colas, Patrick Favetta, Tony Garnier, Peggy Barbe, Mathilde Keck, Daniel Gillet, Alicia Mas, Ali Alejo, Yinyi Yu, Karoly Toth, Getahun Abate, Vincent Roy, Janet Skerry, Kelly S Wetzel, Joshua D Shamblin, Joseph W Golden, Rekha G Panchal, Eric M Mucker, Rajini Mudhasani, Luigi A Agrofoglio, Frederic Iseni, Franck Gallardo

{"title":"Antiviral Activity of the Acyclic Nucleoside Phosphonate Prodrug LAVR-289 against Poxviruses and African Swine Fever Virus.","authors":"Elie Marcheteau, Estelle Mosca, Gaelle Frenois-Veyrat, Sandrine Kappler-Gratias, Laetitia Boutin, Sokunthea Top, Thomas Mathieu, Cyril Colas, Patrick Favetta, Tony Garnier, Peggy Barbe, Mathilde Keck, Daniel Gillet, Alicia Mas, Ali Alejo, Yinyi Yu, Karoly Toth, Getahun Abate, Vincent Roy, Janet Skerry, Kelly S Wetzel, Joshua D Shamblin, Joseph W Golden, Rekha G Panchal, Eric M Mucker, Rajini Mudhasani, Luigi A Agrofoglio, Frederic Iseni, Franck Gallardo","doi":"10.1021/acsinfecdis.5c00169","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00169","url":null,"abstract":"Poxviruses are double-stranded DNA viruses including relevant zoonotic pathogens with high morbidity and potential biological warfare threats. Although African swine fever virus belongs to the Asfarviridae family and is not strictly classified as a Poxviridae member, both fall within the same class of Pokkesviricetes that replicate in the cytoplasm. Among compounds targeting these viruses, acyclic nucleoside phosphonate (ANP) prodrugs are promising inhibitors of viral DNA polymerases. However, some limitations related to their toxicity and the rapid emergence of resistance highlight the need for new antiviral molecules. In this study, we tested a new ANP called LAVR-289. This product effectively inhibits viral replication by targeting a specific domain in the poxvirus DNA polymerase. Using monkeypox virus models, the subcutaneous or oral administration of LAVR-289 demonstrated protective efficacy in infected animals without toxicity. Its in vivo half-life, long on-the-shelf stability and broad-spectrum efficacy make LAVR-289 a promising candidate for further development and stockpiling as a medical countermeasure against dsDNA virus outbreaks. LAVR-289 can be positioned in the context of recurrent viral epidemics, bioterrorism risk, and the emergence of resistant strains in the population.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118358","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}

引用次数: 0

Genome Mining and Chemistry-Driven Discovery of a Cell Wall Lipopeptide Signature for Mycobacterium avium subsp. paratuberculosis Ancestral Lineage. 禽分枝杆菌亚种细胞壁脂肽特征的基因组挖掘和化学驱动发现。副结核的祖先血统。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-21 DOI: 10.1021/acsinfecdis.5c00181

John P Bannantine, Gilles Etienne, Anne Lemassu, Thierry Cochard, Christelle Ganneau, Sandrine Melo, Cyril Conde, Hedia Marrakchi, Sylvie Bay, Franck Biet

{"title":"Genome Mining and Chemistry-Driven Discovery of a Cell Wall Lipopeptide Signature for Mycobacterium avium subsp. paratuberculosis Ancestral Lineage.","authors":"John P Bannantine, Gilles Etienne, Anne Lemassu, Thierry Cochard, Christelle Ganneau, Sandrine Melo, Cyril Conde, Hedia Marrakchi, Sylvie Bay, Franck Biet","doi":"10.1021/acsinfecdis.5c00181","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00181","url":null,"abstract":"Mycobacterium avium subsp. paratuberculosis (Map) causes Johne's disease (JD), a chronic infection responsible for considerable economic losses to dairy industries worldwide. Genetically clonal, Map has evolved into three distinct genetic lineages designated CII, for bovine strains, and SI and SIII, for ovine strains. Previous studies have established that Map does not produce glycopeptidolipids, characteristic of the cell wall surface of mycobacteria belonging to the M. avium complex, but rather sugar-free lipopeptide compounds synthesized by nonribosomal peptide synthetases. In this study, we combined genomic, machine learning, (bio)chemical, and analytical approaches to identify the metabolites biosynthesized by NRPS in the most ancestral SI strains of Map. We thus characterized a lipotripeptide (L3P-2) signature for the SI genetic lineage, demonstrating that the evolution of this Map subspecies has been accompanied by a diversification of the cell wall lipopeptides. Finally, L3P-2 shows promise for improved serological diagnosis of JD.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118362","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}

引用次数: 0

Degradable Hydrophilic Poly(ethylene glycol) Microspheres for the Sustained Delivery of Peptide-Based Antibiotics for Local Anti-infective Therapies. 可降解的亲水聚乙二醇微球用于局部抗感染治疗中持续递送肽类抗生素。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-05-21 DOI: 10.1021/acsinfecdis.5c00208

Laurent Bédouet, Anne Beilvert, Emeline Servais, Florentina Pascale, Saïda Homayra Ghegediban, Julien Namur, Laurence Moine

{"title":"Degradable Hydrophilic Poly(ethylene glycol) Microspheres for the Sustained Delivery of Peptide-Based Antibiotics for Local Anti-infective Therapies.","authors":"Laurent Bédouet, Anne Beilvert, Emeline Servais, Florentina Pascale, Saïda Homayra Ghegediban, Julien Namur, Laurence Moine","doi":"10.1021/acsinfecdis.5c00208","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00208","url":null,"abstract":"Bacterial infections related to medical implants, especially periprosthetic joint infection (PJI), pose a significant clinical challenge. Systemic antibiotic therapy faces limitations, including bacterial resistance, systemic toxicity, and inadequate drug penetration at infection sites. This study investigates a drug delivery strategy using dry, sterile, and hydrophilic degradable microspheres (DrugMic) for extemporaneous antibiotic loading. DrugMic consists of polyethylene glycol (PEG) hydrogels cross-linked with a hydrolyzable cross-linker composed of PEG and varying proportions of lactide and caprolactone. Following microsphere synthesis and e-beam sterilization, extemporaneous antibiotic loading was achieved by rapid mixing of the antibiotic solutions with the sterile microspheres. The study focuses on polymyxins and glycopeptides (vancomycin and teicoplanin) because of their key role in combating the Gram-negative and Gram-positive pathogens increasingly prevalent in PJI, all of which were efficiently loaded through ionic and hydrophobic interactions. The subsequent in vitro drug release lasted between 2 days and 2 weeks, depending on the compositing and degradation rate of the microsphere. Drug release was mainly influenced by antibiotic lipophilicity and degree of microsphere cross-linking. DrugMic protects antibiotics by avoiding exposure to harsh processing conditions such as organic solvents, high temperatures, mechanical shear, and terminal sterilization, which can degrade antibiotics by radiolysis. A rabbit pharmacokinetic study confirmed sustained teicoplanin release after extemporaneous loading onto sterile DrugMic. The DrugMic appears to be a promising degradable platform for the local treatment of PJI with antibiotics that are effective against multidrug-resistant Gram-positive and Gram-negative bacteria.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118360","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}

引用次数: 0