Antimicrobial Agents and Chemotherapy最新文献

{"title":"Safety and pharmacokinetics of CL-197, a potent compound with low cytotoxicity against HIV-1: a randomized, double-blind, placebo-controlled, first-in-human phase 1 clinical trial.","authors":"Yuming Guo, Yonggang Li, Pan Zhao, Jingfeng Bi, Chaoyun Gou, Zhengran Chuai, Shuangjie Yu, Renjie Zhang, Jinfa Du, Yi Ou, Ruonan Xu, Na Guo, Fu-Sheng Wang, Yuanyuan Li","doi":"10.1128/aac.00984-26","DOIUrl":"10.1128/aac.00984-26","url":null,"abstract":"<p><p>HIV infection remains a critical global public health concern. A potential long-acting therapeutic agent, 4'-ethynyl-2-fluoroadenosine analog 1c (CL-197), was investigated in a first-in-human phase 1 clinical trial. This single-center, randomized, double-blind, dose-escalation, placebo-controlled study assessed the safety and pharmacokinetics (PKs) of five doses of CL-197 (1, 10, 30, 60, and 100 mg) in healthy adults aged 18-45 years. The 1 mg group was open-label (<i>n</i> = 4), while the other groups were randomized 4:1 to CL-197 or placebo. The primary endpoints were safety and tolerability. The PK evaluation involved the characterization of systemic exposure parameters (based on plasma drug concentrations and peripheral blood mononuclear cell [PBMC] drug concentrations) and urinary excretion parameters. CL-197 was well tolerated at all dose levels. The most frequently reported adverse reactions were sinus arrhythmia, followed by decreased apolipoprotein B, decreased blood iron, increased triglycerides, and elevated low-density lipoprotein. Plasma PKs showed dose-proportional exposure, with a mean time to maximum plasma concentration (<i>T</i>_max) of 0.50-1.00 h. As the dose increased, the elimination time was prolonged. The plasma drug concentrations were approximately dose-proportional, whereas <i>AUC</i> _0-t and <i>AUC</i> _0-∞ exhibited non-linear characteristics within the range of 1-100mg, with the mean elimination half-life (<i>t</i>_1/2) increasing from 1.39 to 10.20 h across doses. The mean <i>t</i>_1/2 in PBMCs was 61.29 h and 43.80 h in the 30 mg and 60 mg dose groups, respectively, and the median <i>T</i>_max was 12 h. In conclusion, a single administration of CL-197 demonstrated an acceptable safety profile in younger adults. The intracellular CL-197-TP in PBMCs had a long half-life, providing preliminary support for the potential use of extended dosing intervals in further development.<b>CLINICAL TRIALS</b>This study is registered with ClinicalTrials.gov as NCT05944848.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0098426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890784","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> activity profiles and temporal trends in reduced susceptibility to azoles in <i>Coccidioides</i> in the United States.","authors":"Nathan P Wiederhold, Charlotte Bisson, David A Stevens, Chiung-Yu Hung, Jose Lopez-Ribot, Thomas F Patterson, George R Thompson Iii","doi":"10.1128/aac.00744-26","DOIUrl":"10.1128/aac.00744-26","url":null,"abstract":"<p><p>Treatment of symptomatic patients with coccidioidomycosis often involves the use of triazole antifungals. There is concern for reduced susceptibility of <i>Coccidioides</i> to fluconazole, as a high percentage of isolates were previously reported to have elevated fluconazole MICs. We reviewed our recent azole MICs against <i>Coccidioides</i> and examined temporal trends over a 20-year period. Our clinical laboratory database was queried for data against <i>Coccidioides</i> between 2006 and 2025, and trends in GM MICs and the percentage of isolates with elevated MICs to the azoles were assessed. All testing had been performed by broth dilution according to Clinical and Laboratory Standards Institute (CLSI) M38 methods. The results over the 10-year period from 2016 to 2025 were compared to those previously reported by our group from 2001 to 2015. Overall, the results between the two periods showed similar MIC parameters and distributions for fluconazole, itraconazole, posaconazole, and voriconazole, with posaconazole demonstrating the most potent activity, while fluconazole demonstrated reduced susceptibility. Isavuconazole MIC parameters were available during the second period and similar to those of voriconazole. Weak correlations were observed between fluconazole MICs and those of the other azoles. Fluctuations in GM MICs and the percentage of isolates with elevated MICs were observed with fluconazole, itraconazole, and posaconazole, with elevated values observed between 2011 and 2019. Continued surveillance is needed, and outcome data are required to determine if the consistently reduced susceptibility observed with fluconazole or in those infected with strains that have higher MICs results in poorer outcomes in patients with coccidioidomycosis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0074426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886052","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":"Impact of PBP3 insertions and β-lactamase-encoding genes on the susceptibility of <i>Escherichia coli</i> isolates belonging to high-risk clones against aztreonam-avibactam and comparator agents.","authors":"Mariana Castanheira, John H Kimbrough, Maura Karr, Helio S Sader","doi":"10.1128/aac.00129-26","DOIUrl":"10.1128/aac.00129-26","url":null,"abstract":"<p><p>We evaluated the presence and phenotypic impact of PBP3 insertions YRIN (<i>n</i> = 44) and YRIK (<i>n</i> = 18) among 124 <i>Escherichia coli</i> isolates belonging to high-risk lineages selected from 1,471 isolates displaying resistance to β-lactams. PBP3 insertions were detected among 62 isolates. YRIN insertions were detected among isolates belonging to ST167 (<i>n</i> = 23), ST361 (<i>n</i> = 7), ST410 (<i>n</i> = 10), ST617 (<i>n</i> = 1), and ST648 (<i>n</i> = 3), while YRIK insertions were observed in ST405 (<i>n</i> = 9), ST410 (<i>n</i> = 5), and ST617 (<i>n</i> = 4). Aztreonam-avibactam inhibited 90.3% of all isolates from high-risk clones and 80.6% of the isolates harboring PBP3 insertions when applying the EUCAST breakpoints. Aztreonam-avibactam inhibited 66.7% of the YRIK-harboring isolates (MIC_50/90, 2/16 mg/L) and 86.4% of the ones harboring YRIN insertions (MIC_50/90, 1/8 mg/L); however, the susceptibilities to other β-lactams were lower among YRIN isolates (25.6%-60.5%) compared to YRIK (55.6%-88.9%). Overall, ST617 was more resistant to all agents when compared to other STs, regardless of PBP3 insertions or the presence of other examined resistance mechanisms. Acquired β-lactamase genes and OmpC deleterious alterations were present in all isolates. CMY-42, CMY-141, and CMY-145 that have been associated with elevated aztreonam-avibactam MICs were detected among 13 isolates, and 4 (30.8%) were susceptible to this combination. All isolates harboring <i>bla</i>_NDM-5 (<i>n</i> = 37) possessed PBP3 insertions. Aztreonam-avibactam inhibited 83.8% of these isolates. Resistance to aztreonam-avibactam is multifactorial, and singular resistance mechanisms are unable to elevate MIC values to resistant categories. Additionally, lineage-specific contributions to resistance play an important role in the overall development of β-lactam resistance, although these mechanisms appear to function outside the known repertoire of resistance-conferring mutations and warrant further study.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0012926"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910569","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 vivo</i> emergence of ceftazidime/avibactam resistance in <i>Pseudomonas aeruginosa</i> driven by OXA-1381, a novel W157L Ω-loop variant of OXA-2.","authors":"Gloria Pérez-Rodríguez, Lucía González-Pinto, Pablo Aja-Macaya, Carlos Molina-Cáceres, Lucía Sánchez-Peña, Tania Blanco-Martín, Antonio Oliver, Germán Bou, Jorge Arca-Suárez","doi":"10.1128/aac.00584-26","DOIUrl":"10.1128/aac.00584-26","url":null,"abstract":"<p><p>The emergence of ceftazidime/avibactam resistance in an extended-spectrum β-lactamase (ESBL)-producing <i>Pseudomonas aeruginosa</i> isolate during ceftazidime/avibactam therapy was investigated and the underlying mechanisms elucidated. Two sequential isolates recovered before and after the ceftazidime/avibactam treatment were characterized by antimicrobial susceptibility testing, whole-genome sequencing, and functional and biochemical analyses. The initial isolate was susceptible to ceftazidime/avibactam, whereas the later isolate developed resistance (increase in MIC from 2 to 32 mg/L), accompanied by collateral carbapenem susceptibility. Both isolates co-produced a novel BEL variant (designated BEL-5) and an OXA-2 enzyme, encoded by adjacent genes within a class one integron embedded in a 31,623-bp IncP plasmid. The resistant isolate harbored a previously undescribed OXA-2 variant, designated OXA-1381, carrying a W157L substitution in the Ω-loop. Cloning experiments demonstrated that OXA-1381 is an extended-spectrum variant conferring increased resistance to ceftazidime/avibactam and ceftolozane/tazobactam but decreased resistance to carbapenems. Kinetic analyses revealed a marked increase in the affinity and catalytic efficiency of OXA-1381 against ceftazidime and ceftolozane, while showing reduced hydrolytic activity against meropenem, consistent with the observed phenotypic trade-off. Inhibition assays showed similar susceptibility to avibactam for both enzymes, confirming that resistance was driven by enhanced hydrolysis rather than by impaired inhibition. The findings document the <i>in vivo</i> evolution of ceftazidime/avibactam resistance in an ESBL-producing <i>P. aeruginosa</i> background, mediated by structural modification of a narrow-spectrum OXA-2 enzyme. In addition, they highlight the potential of integron-borne genes encoding \"silent\" β-lactamases to evolve under antibiotic pressure and compromise the activity of last-line agents.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0058426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787528","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":"A novel ursodeoxycholic acid derivative exhibits broad-spectrum antiviral activity against influenza A virus and coronaviruses by multiphasic disruption of the viral life cycle.","authors":"Zheng Peng, Haoxing Yuan, Junran Huang, Xinxin Lin, Chan Yang, Gaopeng Song, Shuwen Liu","doi":"10.1128/aac.00284-26","DOIUrl":"10.1128/aac.00284-26","url":null,"abstract":"<p><p>Seasonal influenza virus and human coronaviruses (HCoVs) represent persistent threats to global public health, with current antiviral agents limited by narrow-spectrum activity and the emergence of drug resistance. Multi-stage and multi-target antiviral agents enhance therapeutic efficacy and overcome drug resistance versus single-target therapies by inhibiting multiple key steps of the viral life cycle, such as entry, replication, and release. Here, we characterize a novel ursodeoxycholic acid (UCDA) derivative (U-BSA) as a broad-spectrum antiviral candidate effective against influenza A viruses (H1N1 and H3N2), HCoVs (including HCoV-OC43 and other pseudovirus models), and respiratory syncytial virus (RSV). <i>In vitro</i>, U-BSA exhibited inhibitory activity against H1N1 (half-maximal effective concentration [EC₅₀] = 4.10 µM; selectivity index [SI] > 50), H3N2 (EC₅₀ = 2.41 µM, SI > 40), HCoV-OC43 (EC₅₀ = 9.66 µM, SI > 20), and RSV (EC₅₀ = 6.01 µM, SI > 12). Furthermore, U-BSA conferred significant protection in a lethal influenza infection model <i>in vivo</i>. Mechanistic studies demonstrated that U-BSA interferes with multiple viral life cycles: it disrupts viral attachment, inhibits entry by blocking endosomal acidification, and suppresses virion release. U-BSA rescues virus-induced membrane lipid disorder, revealing that modulation of host membrane homeostasis serves as a critical upstream mechanism underlying its multiphasic antiviral inhibition. This multi-target mode of action represents a significant advance in antiviral strategy, highlighting U-BSA as a promising candidate for developing broad-spectrum antivirals against pan-respiratory virus.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0028426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910516","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":"Functional validation of the <i>Plasmodium falciparum</i> K13 C580Y mutation in recently collected Ethiopian isolates.","authors":"Angana Mukherjee, Ashenafi Bahita Assefa, Christopher V Turlo, Lisa Checkley Needham, Douglas Shoue, Tarrick Qahash, Mahlet Belachew, Dagimawie Tadesse, Enirsie Kassie, Mulu Berihun, Bokretsion G Brhane, Jonathan B Parr, Michael T Ferdig","doi":"10.1128/aac.00495-26","DOIUrl":"10.1128/aac.00495-26","url":null,"abstract":"<p><p>Recent genomic investigation in Ethiopia identified the first detection of the <i>Plasmodium falciparum</i> Kelch13 (K13) C580Y substitution in the Horn of Africa. To assess its functional impact, we introduced C580Y into two recently collected Ethiopian clinical isolates using CRISPR-Cas9 genome editing. Ring-stage survival assays showed significantly elevated <i>in vitro</i> dihydroartemisinin survival in edited parasites relative to isogenic controls, demonstrating that C580Y confers artemisinin tolerance in contemporary Ethiopian parasite genetic backgrounds.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0049526"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910518","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":"High frequency of isavuconazole use over voriconazole for chronic pulmonary aspergillosis: a retrospective observational study on tolerability and therapeutic drug monitoring.","authors":"Federico Fama, Claudia Conflitti, Aurora Civati, Dario Cattaneo, Alessandro Torre, Maria Vittoria Cossu, Silvia Borghetti, Debora Visigalli, Stefania Vimercati, Spinello Antinori, Agostino Riva, Andrea Gori, Marta Colaneri, Marco Schiuma","doi":"10.1128/aac.00892-26","DOIUrl":"10.1128/aac.00892-26","url":null,"abstract":"<p><p>Chronic pulmonary aspergillosis (CPA) is a progressive fungal infection associated with significant morbidity and mortality. Voriconazole, a standard first-line treatment, is limited by poor tolerability, unpredictable pharmacokinetics, and extensive drug-drug interactions. Isavuconazole, a newer triazole with a more favorable safety profile, is currently recommended only as later-line therapy due to limited evidence in CPA. To evaluate the rate of switch from voriconazole to isavuconazole, and to assess the tolerability, pharmacokinetic profile, and drug costs of isavuconazole in a real-world CPA cohort. Single-center retrospective observational study of 40 patients with CPA enrolled at Luigi Sacco University Hospital, Milan, between October 2020 and October 2024, with therapeutic drug monitoring (TDM) throughout treatment. Of 26 patients initiated on voriconazole, 53.8% required a switch to isavuconazole, primarily due to failure to achieve therapeutic plasma concentrations (71.4%) and adverse events. Overall, 70% (28/40) of the cohort ultimately received isavuconazole. Among 233 isavuconazole TDM measurements, 17.6% fell outside the therapeutic range (1-5 mg/L), and 50% of patients required at least one dose adjustment. No patient discontinued isavuconazole due to adverse events, and no treatment failure or relapse occurred among isavuconazole-treated patients. TDM-guided dose reduction to 100 mg daily in 39.3% of patients yielded an estimated drug cost saving of 21.9%. Isavuconazole demonstrated a favorable tolerability profile with no treatment discontinuations due to adverse events. Proactive TDM proved clinically valuable in guiding dose optimization and reducing drug costs, supporting isavuconazole as a viable alternative for long-term CPA management.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0089226"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975623","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":"Clinical use of ampicillin-sulbactam/ceftazidime-avibactam combination therapy for carbapenem-resistant <i>Acinetobacter baumannii</i> complex infections.","authors":"Anna Schneider, Kelly A Cairns, Elke van Gorp, Nenad Macesic, Mariel Beiers, Ben Vezina, Jack Skeggs, Ruzeen Patwa, Matthew Parker, Nhu Quynh Doan, Anton Y Peleg, Iain J Abbott, Sadid F Khan","doi":"10.1128/aac.00587-26","DOIUrl":"10.1128/aac.00587-26","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0058726"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823955","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":"Repeated emergence and fitness heterogeneity of KPC-33 in ST11 <i>Klebsiella pneumoniae</i> under ceftazidime-avibactam pressure.","authors":"Fangling Du, Xinyue Dai, Yuxuan Liu, Chuwen Zhao, Hanxu Hong, Yun Cao, Dandan Wei, Yang Liu","doi":"10.1128/aac.00767-26","DOIUrl":"10.1128/aac.00767-26","url":null,"abstract":"<p><p>Ceftazidime-avibactam (CZA) is an important therapeutic option for infections caused by <i>Klebsiella pneumoniae</i> carbapenemase (KPC)-producing <i>Klebsiella pneumoniae</i>. However, CZA exposure also selects for emergent KPC variants. Their <i>in vivo</i> evolutionary patterns, fitness consequences, and underlying molecular mechanisms remain unclear. We performed a longitudinal multiomics analysis of 35 clonally related ST11 KPC-producing <i>K. pneumoniae</i> isolates collected from eight hospitalized patients during clinical follow-up, most of whom had received CZA therapy. Whole-genome sequencing, antimicrobial susceptibility testing, <i>in vitro</i> competition assays, enzyme kinetic analysis, and transcriptomic sequencing were used to systematically characterize the within-host evolutionary dynamics of KPC variants and the fitness heterogeneity of KPC-33. Multiple KPC variants were identified during longitudinal follow-up, among which KPC-33 was the most frequently detected. Among the seven patients who received CZA treatment, KPC-33 was detected in longitudinal isolates from four patients. It was also identified in patient P3, who had not received CZA, whereas other variants were only sporadically identified. Biochemical analysis showed that KPC-33 exhibited an altered kinetic profile relative to KPC-2, characterized by reduced catalytic turnover and altered substrate affinity. KPC-33 did not exhibit a uniform and pronounced fitness defect but instead showed marked strain-dependent heterogeneity. Strains with higher competitive fitness generally showed only limited transcriptional changes, whereas those with lower fitness were accompanied by broader transcriptional remodeling. In this longitudinal cohort, KPC-33 was repeatedly detected, predominantly under CZA-associated selective conditions. Its fitness consequences were clearly strain background dependent and may be associated with the extent of transcriptional remodeling. These findings provide new evidence for understanding the <i>in vivo</i> evolution of CZA resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0076726"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918409","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":"Mechanistic blockade of RSV infection by a pre-F targeting single-domain antibody-Fc fusion protein.","authors":"Shuang Liu, Xiran Qiu, Shiyu Guo, Liying Wang, Hui Shen, Maomao An","doi":"10.1128/aac.00541-26","DOIUrl":"10.1128/aac.00541-26","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) is a primary cause of acute lower respiratory tract infections in children and the elderly. Despite its clinical impact, effective prophylactic options for RSV remain limited. The prefusion conformation of the RSV fusion (F) protein is a critical target for neutralizing antibodies; however, the specific roles of prefusion versus postfusion states in triggering inflammatory responses have remained unclear. We report the development of Hu3F5, a novel prefusion F-specific single-domain antibody-Fc fusion protein. Hu3F5 demonstrates exceptional neutralizing activity <i>in vitro</i> (IC₅₀: 0.58-9.15 ng/mL), potent <i>in vivo</i> efficacy, and a favorable safety profile in non-human primates. Crucially, our study reveals that the postfusion conformation, rather than the prefusion state, induces IL-6 elevation. Mechanistic analyses show that Hu3F5 neutralizes RSV by locking the F protein in its prefusion state, independent of Fc-mediated effector functions. This physical stabilization prevents the transition to the postfusion conformation, thereby blocking membrane fusion and subsequent inflammatory signaling, as well as the formation of cytopathic syncytia. By identifying the postfusion state as the driver of RSV-induced inflammation, this study positions Hu3F5 as a promising clinical candidate for prophylaxis. Furthermore, it provides new insights into RSV pathogenesis and the efficacy of \"locking\" mechanisms in viral neutralization.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0054126"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975634","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}