Antimicrobial Agents and Chemotherapy最新文献

{"title":"Characterization of new mouse models of acute and chronic <i>Mycobacterium abscessus</i> infection for antimicrobial drug screening.","authors":"Ilham M Alshiraihi, Ha Lam, Brennen T Troyer, Kristina N Tran, Malik Zohaib Ali, Daryl K Conner, Abigail Godelfer, Camron Pearce, Mary Jackson, Marcela Henao-Tamayo, Sara E Maloney Norcross, Bernd Meibohm, Richard E Lee, Mercedes Gonzalez-Juarrero, Andres Obregon-Henao","doi":"10.1128/aac.00475-25","DOIUrl":"10.1128/aac.00475-25","url":null,"abstract":"<p><p><i>Mycobacterium abscessus</i> (MAB), a rapidly growing non-tuberculous mycobacterium, is becoming increasingly recognized as a significant pathogen affecting humans. These bacteria particularly impact individuals with cystic fibrosis (CF), non-CF bronchiectasis, and compromised immune systems. Treating pulmonary infections with MAB is challenging due to the bacteria's inherent and acquired resistance to many antibiotics, including most anti-tuberculosis antibiotics. Antibiotic therapy of MAB infection is lengthy, involves multiple oral and parenteral administered drugs, induces significant toxicity, and, on many occasions, fails to cure. Consequently, developing more effective antibiotics has become a high priority. Preclinical studies to evaluate antibiotic efficacy against MAB are challenging because they fail to establish a progressive and sustained pulmonary infection in commonly used animal models. To address this issue, the course of MAB pulmonary infection was evaluated in 15 immunocompetent or deficient mouse strains. We report bacterial burden and histopathology and classify the models according to their ability to clear or sustain progressive infection beyond 28 days. We also examined the potential of these models for drug screening. Our findings provide a foundation for selecting suitable mouse models of pulmonary MAB infection for drug discovery.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0047525"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147753","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":"Case Commentary: Successful use of olorofim for the treatment of multi-drug-resistant <i>Lomentospora prolificans</i> infection in a child.","authors":"Nathan P Wiederhold","doi":"10.1128/aac.01072-25","DOIUrl":"https://doi.org/10.1128/aac.01072-25","url":null,"abstract":"<p><p><i>Lomentospora prolificans</i> is a multi-drug-resistant filamentous fungus that can cause invasive disease in both immunocompromised and immunocompetent hosts. Current treatment options are limited. Olorofim is an investigational antifungal that demonstrates activity against several different molds, including many that are resistant to other antifungals. The case presented by Fortini et al. (Antimicrob Agents Chemother 69:e00602-25, 2025, https://doi.org/10.1128/aac.00602-25) describes the successful use of olorofim treatment in an 8-year-old who suffered from <i>Lomentospora prolificans</i> tendonitis, synovitis, and osteomyelitis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0107225"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147824","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":"Mass balance, pharmacokinetics, metabolism, and excretion of radiolabeled acoziborole, a potential novel treatment for human African trypanosomiasis, following single microtracer oral dose to humans.","authors":"Jean-Yves Gillon, François Simon, Sharan Sidhu, Mathieu Louis, Delphine Launay, Valérie Wauthier, Marta Pelay-Gimeno, Lotte van Andel, Sabrina Loyau, Sandra Rembry, Estelle Weinling, Antoine Tarral","doi":"10.1128/aac.00580-25","DOIUrl":"https://doi.org/10.1128/aac.00580-25","url":null,"abstract":"<p><p>Acoziborole is an oxaborole 6-carboxamide active against <i>Trypanosoma brucei gambiense</i> and <i>rhodesiense</i>, the parasites responsible for human African trypanosomiasis. This open-label, phase I study in six healthy male participants evaluated the mass balance, pharmacokinetics, metabolism pathways, and excretion of a single oral 960 mg dose of [¹⁴C]-acoziborole. Blood, plasma, and feces were collected for 120 days and urine for 16 days. The excretion balance and systemic exposure of total circulating radioactivity were determined using accelerator mass spectrometry. Metabolism profiling was performed in pools of plasma, urine, and feces. Liquid chromatography coupled with tandem mass spectrometry quantified acoziborole and its metabolite SCYX-3109 in plasma and urine. By Day 60, 87.3% of the total radioactivity had been recovered (10.9% and 74.2% of the total dose in urine and in feces, respectively), with an excretion increment of <1% between Days 59 and 61. Mean ratios of total radioactivity indicated an equivalent distribution between blood cells and plasma. The concentration-time profiles of total radioactivity and acoziborole in plasma were similar. In plasma, acoziborole accounted for 95.1%, an oxidized form of acoziborole for 2.3% of the total radioactivity, while SCYX-3109 was not detected. Seven metabolites (oxidative deboronation, glucuronidation, and mono-oxidation) were detected in urine with individual abundances relative to the dose of 0.1-2.1%; unchanged acoziborole accounted for 0.6%. In feces, acoziborole, SCYX-3109, and two other oxidized or deboronated forms of acoziborole represented 33.6%, 12.3%, and 2.3% of the dose, respectively. Acoziborole showed good absorption, limited metabolism, minimal urinary elimination, and predominant but slow biliary-fecal elimination.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0058025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111891","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":"Noncytotoxic polymyxin derivatives enhance antibiotic action against multidrug-resistant Gram-negative bacteria.","authors":"Danyel Ramirez, Danzel Marie Ramirez, Rajat Arora, Gilbert Arthur, Frank Schweizer","doi":"10.1128/aac.00712-25","DOIUrl":"https://doi.org/10.1128/aac.00712-25","url":null,"abstract":"<p><p>The widespread emergence of multidrug-resistant (MDR) Gram-negative bacteria prompted the reintroduction of polymyxins in the clinic despite their adverse effects. Ongoing research is primarily focused on the development of non-nephrotoxic and -neurotoxic polymyxins as not only standalone agents but also as potentiators that enhance the activity of a partner antibiotic. Safer derivatives of polymyxin B₃, a minor component of polymyxin B, were synthesized and utilized as a potentiator of multiple antibiotics. Compound <b>1</b>, consisting of Dap residues, was nontoxic to kidney cells and is a promising outer membrane permeabilizer that synergized with six different classes of antibiotics against MDR Gram-negative bacteria. Compound <b>1</b> extended the activity spectrum of rifampicin, zoliflodacin, and pristinamycin by lowering the minimum inhibitory concentrations of these antibiotics below their interpretative susceptibility breakpoints in MDR <i>Pseudomonas aeruginosa</i>, <i>Acinetobacter baumannii</i>, <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, and <i>Enterobacter cloacae</i>. Notably, the novel combination of zoliflodacin, a first-in-class antibiotic in phase III trials for gonorrhea, and compound <b>1</b> exhibited potent bactericidal activity in MDR <i>P. aeruginosa</i> and <i>A. baumannii</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0071225"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111889","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":"Evolution of beta-lactam resistance causes fitness reductions and several cases of collateral sensitivities in the human pathogen <i>Haemophilus influenzae</i>.","authors":"Sabine Petersen, Margo Diricks, Christian Utpatel, Hinrich Schulenburg, Matthias Merker","doi":"10.1128/aac.00576-25","DOIUrl":"https://doi.org/10.1128/aac.00576-25","url":null,"abstract":"<p><p>The evolution of antimicrobial-resistant pathogens poses a global health threat, and it is unclear if evolutionary trajectories to resistance lead to predictable phenotypes. We analyzed antimicrobial resistance (AMR) evolution in the human pathogen <i>Haemophilus influenzae</i> in controlled evolution experiments with increasing concentrations of either ampicillin, cefotaxime, or ceftriaxone. We isolated 315 clones from different time points of six independent experiments and characterized changes in genome sequences, bacterial fitness, and minimum inhibitory concentrations (MICs) to 14 antibiotics. Resistance evolution under ampicillin and cefotaxime was mainly driven by mutations in the <i>ftsI</i> gene, encoding the penicillin-binding protein 3. However, ceftriaxone exposure repeatedly selected for amino acid substitutions in the outer membrane protein P2 (OmpP2). Some OmpP2 mutants reproducibly showed phenotypic heterogeneity not only for ceftriaxone but also for fluoroquinolones, rifampicin, and tetracycline. Bacterial fitness assessments revealed trade-offs between resistance-associated mutations and growth, though no systematic correlation of MIC increase and growth deficit was detected. Over 50% of the selected clones became more susceptible to aminoglycosides, clarithromycin, and colistin, while some mutation patterns resulted in cross-resistance to meropenem and fluoroquinolones. Overall, beta-lactam antibiotics reproducibly selected mutants with increased MICs, but evolutionary pathways and resulting phenotypes remain unpredictable. These findings highlight the complexity of resistance evolution and suggest that future AMR treatment strategies may need to consider strain-specific and collateral effects more closely.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0057625"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111915","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":"Thienopyrimidine amide analogs target MmpL3 in <i>Mycobacterium tuberculosis</i>.","authors":"Vanessa Pietrowski Baldin, Christopher L Harding, Diana Quach, Joseph Sugie, Joe Pogliano, Tanya Parish","doi":"10.1128/aac.00980-25","DOIUrl":"10.1128/aac.00980-25","url":null,"abstract":"<p><p>The identification of novel agents with mechanisms of action distinct from those currently utilized in tuberculosis treatment remains a significant challenge. The mycobacterial protein MmpL3 has emerged as a promising drug target due to its essential role in the synthesis of the cell wall of <i>Mycobacterium tuberculosis</i>. We previously identified novel thienopyrimidine amides(TPAs) with good anti-tubercular activity. We profiled a subset of TPAs, determining activity against intracellular bacteria and bactericidal activity against replicating bacteria. We ran assays to determine the mode of action by measuring cell wall stress, ATP production, and bacterial cytological profiling. We determined activity against a strain of M. tuberculosis with mutations in MmpL3. We isolated and sequenced resistant mutants. We tested five analogs against a strain of <i>M. tuberculosis</i> with mutations in MmpL3 and determined that they lost potency. Analogs induced P_iniBAC, a reporter for cell wall stress, and led to an ATP boost characteristic of cell wall inhibitors. Bacterial cytological profiling of a representative compound revealed a morphological profile consistent with other MmpL3 inhibitors. Together, our data support MmpL3 as the most probable drug target for the TPA analogs and add to the growing list of scaffolds that can inhibit this vulnerable transporter.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0098025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111834","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":"Emergence of azithromycin and ciprofloxacin non-susceptible genotype 4.2.2 <i>S</i>. Typhi in Fiji.","authors":"Ashwini Vinod, Andrew J Hayes, Yogeshni Chandra, Sonika Kaajal Nair, Tashyam Pillay, Farieya Fayza Khan, Shalini Goundar, Luse Dulaki Kalou, Khushnuma Khan, Maria Borua Anise, Mary Valcanis, Xinwei Ruan, Shalini Singh, Jessica Barnden, Raphaël M Zellweger, Alumita Vuakanisakea, Kylie Hui, Lisa J Ioannidis, Kim Mulholland, Richard A Strugnell, Benjamin P Howden, Mark R Davies, Aneley Getahun Strobel","doi":"10.1128/aac.00588-25","DOIUrl":"https://doi.org/10.1128/aac.00588-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0058825"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111923","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":"Acquired amphotericin B resistance attributed to a mutated <i>ERG3</i> in <i>Candidozyma auris</i>.","authors":"Lauryn Massic, Laura A Doorley, Sarah J Jones, Irene Richardson, Danielle Denise Siao, Lauren Siao, Philip Dykema, Chi Hua, Emily Schneider, Christina A Cuomo, P David Rogers, Stephanie Van Hooser, Josie E Parker, Steven L Kelly, David Hess, Jeffrey M Rybak, Mark Pandori","doi":"10.1128/aac.00601-25","DOIUrl":"10.1128/aac.00601-25","url":null,"abstract":"<p><p>First identified in 2009, <i>Candidozyma auris</i> (formerly <i>Candida auris</i>) is an emerging multidrug-resistant fungus that can cause invasive infections with a crude mortality rate ranging from 30 to 60%. Currently, 30-50% of <i>C. auris</i> isolates are intrinsically resistant to amphotericin B. In this study, we characterized a clinical case of acquired amphotericin B resistance using whole-genome sequencing, a large-scale phenotypic screen, comprehensive sterol profiling, and genotypic reversion using CRISPR. Data obtained in this study provide evidence that a deletion resulting in a frameshift in <i>ERG3</i> significantly contributes to the observed resistant phenotype, and a nonsense mutation in <i>ERG4</i> may more modestly contribute to resistance. Characterization of this isolate also revealed that a fitness cost is associated with the abrogation of ergosterol production and its replacement with other late-stage sterols. This article presents a clinical case description of amphotericin B resistance from a frameshift mutation in <i>ERG3</i> in <i>C. auris</i> and marks an advancement in the understanding of antifungal resistance in this fungal pathogen.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0060125"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111912","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":"<i>In vitro</i> exposure to clofazimine can select for delamanid and pretomanid resistance in <i>Mycobacterium tuberculosis</i>.","authors":"Praharshinie Rupasinghe, Nabila Ismail, Wim Mulders, Robin M Warren, Lavania Joseph, Dumisani Ngcamu, Thabisile Gwala, Shaheed V Omar, Jens Vereecken, Bouke C de Jong, Leen Rigouts, Emanuele Borroni, Daniela M Cirillo, Thomas Schön, Paolo Miotto, Claudio U Köser","doi":"10.1128/aac.01113-25","DOIUrl":"https://doi.org/10.1128/aac.01113-25","url":null,"abstract":"<p><p><i>In vitro</i> experiments with <i>Mycobacterium tuberculosis</i> showed that clofazimine exposure selected for delamanid and pretomanid resistance and mutations in <i>fbiA</i>, <i>fbiC</i>, or <i>fbiD</i>-after the acquisition of <i>Rv0678</i> mutations where this could be determined. Whether this is also possible <i>in vivo</i> and in an <i>Rv0678</i> wild-type background has to be studied further. Based on the available evidence, however, we propose that nitroimidazole resistance should not be considered an exclusion criterion for the use of clofazimine.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0111325"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111896","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":"Epetraborole pharmacokinetics/pharmacodynamics in the hollow fiber system model of <i>Mycobacterium tuberculosis</i>.","authors":"Sanjay Singh, Megan Devine, Tawanda Gumbo, Shashikant Srivastava","doi":"10.1128/aac.00481-25","DOIUrl":"https://doi.org/10.1128/aac.00481-25","url":null,"abstract":"<p><p>In the hollow fiber system model of tuberculosis (TB), the ratio of area under the concentration-time curve to MIC (AUC_0-24/MIC) of 327.1 was identified as the epetraborole optimal exposure target for <i>Mycobacterium tuberculosis</i> kill. Monte Carlo simulation experiments showed that even the intravenous dose of 1,500 mg/twice daily would fail in the majority of patients, and the dose needed for good efficacy for TB may likely not be safe for patients.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0048125"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111926","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}