Antimicrobial Agents and Chemotherapy最新文献

{"title":"Assessment of TB47 as a potential novel therapeutic agent: <i>in vitro</i> and <i>in vivo</i> efficacy against <i>Mycobacterium leprae</i>.","authors":"Gabriel Henrique Fioroni Furlan, Diego Augusto Souza Oliveira, Daniele Ferreira De Faria Bertoluci, Tiago Araujo Gomes, Jonatas Perico, Bruna Leticia Martins, Dejair Caetano Do Nascimento, Suzana Madeira Diorio, Cleverson Teixeira Soares, Shuai Wang, Tianyu Zhang, Patricia Sammarco Rosa, Flavio Alves Lara, Ana Carla Pereira Latini","doi":"10.1128/aac.00318-25","DOIUrl":"10.1128/aac.00318-25","url":null,"abstract":"<p><p>Leprosy is a chronic infectious disease caused by <i>Mycobacterium leprae</i> and <i>Mycobacterium lepromatosis</i>. The treatment typically involves multidrug therapy comprising dapsone, clofazimine, and rifampicin for 6-12 months. TB47 is a new inhibitor of the mycobacterial electron transport chain (ETC), disrupting ATP production in bacteria. This study investigated the <i>in vitro</i> and <i>in vivo</i> antimicrobial effects of TB47 on <i>M. leprae. In vitro</i> assays employed IDE8 tick cells infected with <i>M. leprae</i>, showing that after 30 days of infection, 5 ng/mL of TB47 treatment significantly impaired bacillary growth. For <i>in vivo</i> assays, BALB/c mice were infected with <i>M. leprae</i> and subjected to different treatments with varying doses of TB47 combined or not with clofazimine. Treatments were administered weekly for 90 days (13 times). The effects were assessed immediately after treatment, as well as at 120 and 210 days post-treatment. Results showed that 100 and 10 mg/kg of TB47 combined with 5 mg/kg clofazimine exhibited a bactericidal effect on <i>M. leprae</i> in all time points evaluated, in contrast with clofazimine monotherapy, for which the bactericidal effect was observed only 210 days post-treatment. TB47 monotherapy had a bacteriostatic effect immediately after treatment, but replication resumed at later evaluation points. Histopathological evaluation supported these findings. Combining dose-dependent TB47 with clofazimine showed an additive bacteriostatic and bactericidal effect on <i>M. leprae</i>, suggesting an advantageous pharmacokinetic and pharmacodynamic profile. Further research into mycobacterial ETC inhibitors could significantly impact leprosy management by providing more effective and shorter treatment options.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0031825"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688758","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":"Mutations in transcription factors that confer fluconazole resistance also confer reduced susceptibility to manogepix in <i>Candida auris</i> (<i>Candidozyma auris</i>), <i>Candida albicans</i>, <i>Candida parapsilosis</i>, and <i>Candida glabrata</i> (<i>Nakaseomyces glabratus</i>).","authors":"Katherine S Barker, Hoja P Patterson, Joachim Morschhäuser, Christina A Cuomo, Nathan P Wiederhold, P David Rogers","doi":"10.1128/aac.00680-25","DOIUrl":"10.1128/aac.00680-25","url":null,"abstract":"<p><p>The fungal pathogen <i>Candida auris</i> is of global concern due to high levels of multidrug resistance and its propensity to cause infectious outbreaks. Over 90% of isolates are resistant to fluconazole, the most commonly prescribed antifungal worldwide. Fluconazole resistance is multifactorial with many isolates carrying mutations in the gene encoding the transcriptional regulator Tac1B, leading to increased expression of the gene encoding the ATP-binding cassette (ABC) transporter Cdr1. Recently, a study in <i>C. auris</i> examining mechanisms of <i>in vitro</i>-evolved reduced susceptibility to manogepix, a promising antifungal agent currently in clinical trials, found a <i>TAC1B</i> mutation that confers reduced manogepix and fluconazole susceptibility. We hypothesized that mutations in <i>C. auris TAC1B</i> and similar transcription factors in other <i>Candida</i> species that confer fluconazole resistance might also confer reduced susceptibility to manogepix. We measured manogepix susceptibilities for selected isolates and strains and found that mutations in <i>C. auris TAC1B</i>, <i>C. albicans</i> and <i>C. parapsilosis TAC1</i>, and <i>C. glabrata PDR1</i> confer reduced manogepix susceptibility in a manner dependent on ABC transporters, such as Cdr1. Our findings raise the possibility of fluconazole and manogepix cross-resistance for clinical isolates harboring mutations in these genes.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0068025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688765","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":"Omadacycline exhibits anti-inflammatory properties and improves survival in a murine model of post-influenza MRSA pneumonia.","authors":"Sumiko Gomi, Emily Price, Hailey Burgoyne, Sabrina Faozia, Eva Katahira, Eric McIndoo, Anyauba A Nmaju, Kavita Sharma, Ali Aghazadeh-Habashi, Amy E Bryant, Dennis L Stevens, Jessica V Pierce, Alisa W Serio, Sarah E Hobdey","doi":"10.1128/aac.00469-25","DOIUrl":"10.1128/aac.00469-25","url":null,"abstract":"<p><p>Post-influenza <i>Staphylococcus aureus</i> pneumonia, particularly methicillin-resistant <i>S. aureus</i> (MRSA), remains a major cause of mortality, highlighting the urgent need for newer therapeutic options. Omadacycline is an aminomethylcycline antibiotic that has demonstrated efficacy against MRSA across many infection models, but its potential in post-influenza A virus (IAV)-MRSA pneumonia remains unexplored. Using a murine model of this infection, we evaluated the effects of omadacycline and a comparator antibiotic, linezolid, on survival, inflammation, bacterial load, toxin production, and lung histopathology. In survival studies, omadacycline matched the effectiveness of oral linezolid at clinically relevant doses. In addition, both antibiotics, particularly omadacycline, attenuated the production of multiple pro-inflammatory cytokines and reduced neutrophil infiltration in the lungs, independent of their effects on pulmonary microbial burden, suggesting an immunomodulatory mechanism of action. Panton-Valentine leukocidin (PVL) toxin production <i>in vitro</i> and <i>in vivo</i> was also assessed, and while the role of PVL in this murine model remains unclear, both agents reduced PVL production. These findings provide the first preclinical demonstration of <i>in vivo</i> efficacy for omadacycline against IAV-MRSA pneumonia and its ability to modulate the host immune response, thereby reducing the excessive inflammation that is linked to mortality in this disease state. Further investigation into the precise interplay between omadacycline and immunomodulation in this disease state is warranted.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0046925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774583","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":"VH3810109 (N6LS) broadly neutralizing antibody safety, pharmacokinetics, and anti-drug antibody incidence in adults without HIV: phase 1 SPAN study results.","authors":"Peter A Leone, Jan Losos, Paul Wannamaker, Riccardo D'Agostino, Michael Warwick-Sanders, Gabriela L Ghita, Viviana Wilches, Christina Donatti, Kathryn Brown, Yash Gandhi","doi":"10.1128/aac.00258-25","DOIUrl":"10.1128/aac.00258-25","url":null,"abstract":"<p><p>The CD4-binding site antibody VH3810109 (N6LS) demonstrated broad and potent neutralization activity <i>in vitro</i> and robust antiviral activity in people with HIV-1. We report safety, tolerability, pharmacokinetics, and anti-drug antibody (ADA) incidence for subcutaneous (SC) and intravenous (IV) N6LS. Safety and pharmacokinetics of a single dose of VH3810109 (also known as GSK3810109), administered either subcutaneously (SC) with rHuPH20 or intravenously (IV) [SPAN]) was an open-label, three-part, phase 1 study evaluating single-dose N6LS in adults without HIV (part 1, 20 mg/kg SC + recombinant human hyaluronidase PH20 [rHuPH20] 2,000 U/mL; part 2, 60 mg/kg IV; part 3, 3,000 mg SC + rHuPH20 2,000 U/mL). Over 24 weeks, adverse events (AEs), injection site reactions (ISRs), pharmacokinetics, and ADAs were monitored. Twenty-four participants (8/part) were enrolled and received a single N6LS dose. Overall AE incidence between SC doses was similar and higher compared with IV, driven by ISRs. No ISRs were reported for IV N6LS; for SC, 15/16 participants reported ISRs, and 17/32 events were grade 3 (all injection site erythema). All ISRs resolved without sequelae or treatment. All participants rated local reactions and pain as acceptable. No serious AEs or deaths occurred. Pharmacokinetics were as expected for a broadly neutralizing antibody; median terminal half-life ranged from 43 to 47 days. No ADAs were observed after IV N6LS (0/8); 5/16 participants had treatment-emergent ADAs after SC N6LS; however, a clear impact on pharmacokinetics was observed in only one participant. N6LS administered IV or SC + rHuPH20 had a favorable safety profile and was well tolerated. Results support the ongoing development of N6LS 3,000 mg SC + rHuPH20 and 60 mg/kg IV into phase 2b.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT05291520).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0025825"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688770","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":"Pharmacokinetics and safety of single and repeat doses of ceftibuten in healthy participants: a phase 1 dose escalation study.","authors":"Mary Beth Dorr, Carlos Fernando de Oliveira, Jeroen van de Wetering, Kathryn Lowe, Philip Sabato, Gregory Winchell, Hongzi Chen, Paul C McGovern","doi":"10.1128/aac.00087-25","DOIUrl":"10.1128/aac.00087-25","url":null,"abstract":"<p><p>Ledaborbactam etzadroxil, the prodrug of the active β-lactamase inhibitor ledaborbactam, is being developed in combination with ceftibuten to treat serious infections caused by drug-resistant Enterobacterales. This study evaluated the safety and pharmacokinetics of ceftibuten in healthy adults at anticipated higher doses required, in combination with ledaborbactam etzadroxil, to treat Enterobacterales infections. Thirty-six participants (<i>n</i> = 12 per cohort [ceftibuten <i>n</i> = 9, placebo <i>n</i> = 3]) received a single oral dose of ceftibuten (400, 800, or 1,200 mg) or matched placebo on day 1. Following a one-day washout, the same participants received repeat oral doses of ceftibuten (400 mg once daily, 400 mg every 12 hours [q12h], or 400 mg q8h) for 10 days. Of the 36 participants, 25 (ceftibuten 67%, placebo 78%) reported 65 treatment-emergent adverse events (TEAEs). Nausea (22%), headache (15%), and fatigue (15%) were the most reported TEAEs among ceftibuten-treated participants. No participant experienced serious adverse events or discontinuations due to TEAEs. In both single- and multiple-dose cohorts, cis-ceftibuten isomer exposure was dose-proportional for areas under the curve (AUCs) but less than dose-proportional for maximum concentrations (<i>C</i>_max). Low levels of cis-ceftibuten accumulation were observed at steady state, with accumulation ratios of 1.06, 1.09, and 1.24 for the 400 mg once daily, q12h, and q8h cohorts, respectively. Cis-ceftibuten and trans-ceftibuten recovery in urine was 47% and 6%, respectively, following a single dose of 1,200 mg.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04314206.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0008725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783328","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":"Driving factors for beta-lactam resistance gene amplification during <i>de novo</i> resistance evolution in <i>E. coli</i>.","authors":"Luyuan Nong, Xinwei Liu, Xinyu Wang, Wim de Leeuw, Martijs Jonker, Stanley Brul, Benno Ter Kuile","doi":"10.1128/aac.00441-25","DOIUrl":"10.1128/aac.00441-25","url":null,"abstract":"<p><p>Long-term exposure of <i>E. coli</i> to non-lethal step-wise increasing concentrations of beta-lactam antibiotics induces high levels of resistance that can be accompanied by amplification of a chromosomal fragment around the <i>ampC</i> gene. We compared the amplification of the <i>ampC</i> fragment in the wild type, an <i>ampC</i> knockout mutant, a mutant in which the <i>ampC</i> gene was replaced by a tetracycline resistance gene <i>tet(B</i>), and a strain in which the <i>ampC</i> has been translocated. When <i>ampC</i> was removed, no amplification occurred at the original <i>ampC</i> location, but DNA fragments were amplified around the genes coding for efflux pump AcrAB and the multiple antibiotic resistance operon MarRAB. When <i>tet(B</i>) replaced <i>ampC</i>, exposure to tetracycline induced amplification of comparable fragments, while exposure to amoxicillin induced duplication of a larger fragment elsewhere. When <i>ampC</i> was translocated, a fragment around it at the new location was amplified. The importance of the presence but not of the location within the chromosome of the resistance genes for the amplification process indicates that the mechanisms are neither gene nor location specific. Without the relatively efficient resistance gene <i>ampC</i>, duplication and amplification occur around <i>acrAB</i> and <i>marRAB</i> that code for amoxicillin and tetracycline resistance factors. These duplications and amplifications are prevented by <i>ampC</i> amplification.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0044125"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688760","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":"Subgroup-based model selection to improve the prediction of vancomycin concentrations.","authors":"Hanna Kadri Laas, Tuuli Metsvaht, Kadri Tamme, Juri Karjagin, Kristiina Naber, Artjom Afanasjev, Carmen Tiivel, Irja Lutsar, Hiie Soeorg","doi":"10.1128/aac.00174-25","DOIUrl":"10.1128/aac.00174-25","url":null,"abstract":"<p><p>Individualized dosing of vancomycin is recommended, model-informed precision dosing (MIPD) being the preferred method to improve efficacy and limit toxicity. However, its implementation poses challenges, including model selection and initiation dose determination. We developed a model selection tool (MST) and evaluated its potential to improve concentration prediction precision and reduce bias. Retrospective data from adult intensive care unit patients receiving intravenous vancomycin were collected and divided into training and validation data sets. Population predictions from published one-compartment models were computed, and the universally best-performing model (UBM) was selected. A genetic algorithm was used to create an MST. The ability to forecast the third concentration based on previous concentrations was evaluated. A total of 148 vancomycin treatment episodes were included in training and 67 in the validation data set. The MST showed 12% and 6% improved precision compared to the UBM in training and validation data sets, respectively (mean absolute percentage prediction error [mean PAPE] 22.8% vs 26.0% and 28.4% vs 30.2%). The UBM exhibited lower bias in both training and validation data sets (mean percentage prediction error [mean PPE] 5.8% vs 4.7% and -2.8% vs -1.5%, respectively). The MST showed improved performance in predicting the third concentration based on previous concentrations. In both data sets, accuracy was the best/highest when two prior measured concentrations were used (mean PAPE and PPE 17.0% and -3.0% in training and 18.9% and -1.0% in validation data set). Overall, the MST has the potential to enhance vancomycin dosing accuracy from the first dose and simplify model selection, facilitating the utilization of MIPD in clinical practice.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0017425"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688769","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":"<i>Acinetobacter baumannii</i>: much more than a human pathogen.","authors":"Santiago Castillo-Ramírez, Alejandro Aguilar-Vera, Ayush Kumar, Benjamin Evans","doi":"10.1128/aac.00801-25","DOIUrl":"10.1128/aac.00801-25","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is a major human nosocomial pathogen. Due to this, a significant amount of knowledge has been gained about human clinical isolates over a substantial period of time. More recently, studies have begun to pay attention to non-human isolates of <i>A. baumannii</i>. In reviewing these studies, we highlight some major trends. First, <i>A. baumannii</i> has been found in a variety of sources/hosts: from diverse types of animals, to food products, to plants and even aquatic environments. Second, considering the molecular epidemiology of <i>A. baumannii</i>, two scenarios are possible. One implies transmission between human and non-human populations, and this has been described in several international clones (ICs): IC1, IC2, IC5, IC7, and IC8. In the other scenario, human populations are well differentiated from non-human populations, and there is no exchange between them. Third, in terms of antibiotic resistance in the non-human populations, these populations tend to have fewer antibiotic resistance genes, mostly intrinsic in nature. However, when non-clinical bacterial populations come into closer contact with humans, the antibiotic resistance profiles of the non-human bacterial population become more similar to those of clinical populations. Also, there are some instances of non-human isolates showing extensive drug resistance phenotypes. By far, the least studied aspect is the virulence potential of <i>A. baumannii</i> from non-human sources. A small number of studies suggest that some non-human isolates can be as virulent as the human isolates. Finally, we discuss gaps in knowledge and future research avenues when considering non-human populations of <i>A. baumannii</i> and their relationship with human populations.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0080125"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706075","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":"Fractional curative killing of pyronaridine or artesunate combinations with tafenoquine, 4-aminoquinolines, or azithromycin in a murine malaria-luciferase model.","authors":"Gayoung Lee, Janessa Sochima Aneke, David J Sullivan","doi":"10.1128/aac.00247-25","DOIUrl":"10.1128/aac.00247-25","url":null,"abstract":"<p><p>Malaria drug interactions in cytostatic or inhibitory <i>in vitro</i> assays or suppression models <i>in vivo</i> can be different than curative killing interactions. In the pharmacodynamic high parasitemia <i>Plasmodium berghei</i> ANKA-luciferase mouse blood-stage model, we investigated curative interaction analysis of multiple, daily dosed, short half-life, artesunate or single-dose, long half-life, pyronaridine against three single-dose, long half-life, quinolines-chloroquine, amodiaquine, and tafenoquine. Positive or negative parasiticidal activity measured by parasite reduction rate in the days post-treatment correlated nonspecifically to final curative interactions. Tafenoquine/artesunate and pyronaridine/amodiaquine also had fractional combination curative doses of 0.83 and 0.93, with the rest of the interactions closer to neutral at 0.9-1.1. All tested combinations are in the additive drug interaction range. Time to return of initial parasitemia in subcurative regimens was also imprecise for the prediction of cure with combinations. Short blood half-life azithromycin, requiring multiple daily doses, was additive to artesunate or pyronaridine in fractional curative dose combination killing. Murine malaria high parasitemia drug interactions at the curative metric <i>in vivo</i> are a potential benchmark for human studies.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0024725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752111","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":"A rational approach to discovering new persister control agents.","authors":"Sweta Roy, Zeynep S Cakmak, Sheila Priscilla Kyeremeh, Shikha Nangia, Juntao Luo, Dacheng Ren","doi":"10.1128/aac.01814-24","DOIUrl":"10.1128/aac.01814-24","url":null,"abstract":"<p><p>Conventional antibiotic drug discovery selects leads based on bacterial growth inhibition. This approach is ineffective against growth-arrested persister cells. When the treatment stops, persister cells revert to normal cells, causing the infection to relapse. To address the challenge of persistent infections, a paradigm shift in antibiotic development is needed to identify new leads that can eradicate dormant cells. Based on our foundational study, we recently proposed a set of principles for developing new persister killing agents. Here, we report the discovery of new leads that are effective against persister cells using a tailored chemoinformatic clustering algorithm based on these principles. We focused on persister penetration using a small compound library that has known antimicrobial activities against normal cells. Experimental testing of eleven compounds identified from clustering led to the discovery of five new compounds that can effectively penetrate and kill persister cells of <i>Escherichia coli</i> HM22. The top leads were further tested and also found active against persister cells of <i>Pseudomonas aeruginosa</i> and uropathogenic <i>E. coli</i> (UPEC), as well as UPEC biofilms and biofilm-associated persister cells. This rather high yield demonstrates the potential of this new rational approach in identifying effective agents against dormant cells, a root cause of persistent infections that is largely missed in conventional screening.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0181424"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752134","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}