Antimicrobial Agents and Chemotherapy最新文献

{"title":"Synergistic activity of RSL3 and Pyrimethamine to inhibit the proliferation of <i>Plasmodium falciparum</i>.","authors":"Vella Nikolova, Karen Linnemannstöns, Anastasiia Zahoruiko, Markus Ganter, Carsten G Lüder, Matthias Dobbelstein","doi":"10.1128/aac.00471-25","DOIUrl":"10.1128/aac.00471-25","url":null,"abstract":"<p><p>Malaria tropica, caused by <i>Plasmodium falciparum</i> (<i>P. falciparum</i>), remains a global health challenge with limited therapeutic options. In mammalian cells, the small-molecule compound RAS-selective lethal 3 (RSL3) induces ferroptosis via lipid peroxidation. In this study, we demonstrate that RSL3 synergizes with Pyrimethamine, an inhibitor of <i>P. falciparum</i> dihydrofolate reductase (DHFR), to suppress parasite proliferation in red blood cells (RBCs). A similar synergistic effect was observed with Cycloguanil, a structural analog of Pyrimethamine, but not with other DHFR inhibitors or alternative agents that induce ferroptosis in nucleated mammalian cells. Notably, Ferrostatin-1, an antagonist of lipid peroxidation, largely failed to rescue parasite growth in the presence of RSL3, possibly suggesting a mechanism distinct from canonical ferroptosis. These findings suggest that the synergy may involve unidentified targets of RSL3 and Pyrimethamine in <i>P. falciparum</i>, divergent from those described in mammalian systems. Moreover, RSL3 and related compounds could serve as promising adjuvants to enhance the antimalarial efficacy of Pyrimethamine and potentially overcome drug resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0047125"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871047","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":"Preclinical evaluation of tridecaptin M: <i>in vitro</i> and <i>in vivo</i> efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics.","authors":"Vrushali Raka, Manoj Jangra, Parminder Kaur, Rajneesh Dadwal, Shubhangi Kansal, Archana Angrup, Pallab Ray, Hemraj Nandanwar","doi":"10.1128/aac.01083-25","DOIUrl":"10.1128/aac.01083-25","url":null,"abstract":"<p><p>The escalating threat of antimicrobial resistance (AMR), particularly among gram-negative pathogens, necessitates the development of novel therapeutic agents. Tridecaptins, a class of non-ribosomally synthesized lipopeptides with a novel mode of action, have garnered renewed interest in the fight against AMR. Our group previously identified tridecaptin M, a compound with a promising safety profile, prompting further investigation into its efficacy and preclinical characteristics. Here, we show that tridecaptin M exhibits potent activity against multidrug-resistant (MDR) <i>Klebsiella pneumoniae</i> and <i>Escherichia coli</i> without cross-resistance to colistin. It effectively inhibits biofilm formation and disrupts 50% of established biofilm at 10 µg/mL. Tridecaptin M demonstrates a favorable safety profile, as it does not inhibit the cardiac hERG channel and shows minimal interaction with cytochrome P450 enzymes, with no IC₅₀ detected up to 44.6 µg/mL. <i>In vivo</i> toxicity studies via subcutaneous administration confirm its safety up to 600 mg/kg, whereas intravenous administration reveals acute toxicity at ≥30  mg/kg, with biochemical evidence of skeletal muscle, cardiac, and hepatic involvement. In mouse infection models using a colistin-resistant MDR strain of <i>K. pneumoniae</i> reveal the <i>in vivo</i> potential of tridecaptin M and a dose-dependent efficacy at 10 mg/kg, 20 mg/kg, 50 mg/kg, and 100 mg/kg doses, showing a non-linear relationship. Tridecaptin M is metabolized by liver microsomes, with low clearance, and pharmacokinetic analysis in rats indicates favorable attributes, with a terminal half-life (T₁/₂) of 3.65 h intravenously and 8.81 h subcutaneously. Collectively, these data support the continued preclinical development of tridecaptin M as a promising candidate for treating severe gram-negative infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0108325"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038979","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":"In memoriam: George L. Drusano.","authors":"Cesar A Arias","doi":"10.1128/aac.01045-25","DOIUrl":"10.1128/aac.01045-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 10","pages":"e0104525"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197477","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":"Combinations comprising dual β-lactams and a β-lactamase inhibitor achieve optimal synergistic inhibition of <i>Mycobacterium abscessus</i> growth.","authors":"Binayak Rimal, Yi Xie, Chandra M Panthi, Kaylyn L Devlin, Kimberly E Beatty, Gyanu Lamichhane","doi":"10.1128/aac.00127-25","DOIUrl":"10.1128/aac.00127-25","url":null,"abstract":"<p><p>The historical model, which posits that β-lactams inhibit bacterial growth while β-lactamase inhibitors (BLIs) merely protect β-lactams from enzymatic degradation, fails to fully explain their activity against <i>Mycobacterium abscessus</i> (<i>Mab</i>). This study demonstrates that synergistic effects extend beyond the traditional one β-lactam + one BLI paradigm, refuting the oversimplified mechanistic framework. First, β-lactam-based BLIs such as clavulanic acid, sulbactam, and tazobactam exhibit intrinsic antibacterial activity against <i>Mab</i>. These agents synergized not only with β-lactams but also with one another, undermining their historical classification as mere β-lactamase inhibitors. The data indicate that their activity is not limited to inhibiting β-lactamases but extends to directly targeting critical bacterial processes. Second, dual β-lactam combinations exhibit synergism against <i>Mab</i> even in the absence of BLIs. For example, despite being rapidly hydrolyzed by the native β-lactamase Bla_Mab, amoxicillin demonstrates strong synergism with β-lactams such as imipenem or ceftaroline. This suggests that the second β-lactam either acts as a functional BLI surrogate or targets complementary pathways. Supporting this, experiments using penicillin- and carbapenem-based probes revealed that β-lactams bind to multiple <i>Mab</i> proteins simultaneously, reinforcing the idea that their synergy arises from targeting complementary essential proteins. Finally, triple combinations comprising dual β-lactam and one BLI, such as amoxicillin + ceftaroline + avibactam, achieved very high synergy, underscoring the complementary roles of dual β-lactams and BLIs. The evidence in this study necessitates a revised model that can more accurately explain the activities of β-lactams and BLIs and underscores the potential for optimizing β-lactam/BLI regimens against <i>Mab</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0012725"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854330","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":"Frequencies of molecular markers of drug resistance in the context of two different Seasonal Malaria Chemoprevention (SMC) treatment regimens in the Koulikoro health district, Mali.","authors":"Bourama Traore, Fousseyni Kane, Mahamoudou Toure, Marie Helene Munck Jørgensen, Daouda Sanogo, Soumba Keita, Moussa Keita, Nafomon Sogoba, Kathryn Shaw-Saliba, Mahamadou Diakite, Jeffrey G Shaffer, Michael Alifrangis, Helle Hansson, Seydou Doumbia","doi":"10.1128/aac.01806-24","DOIUrl":"10.1128/aac.01806-24","url":null,"abstract":"<p><p>With growing concern about parasite resistance to sulfadoxine-pyrimethamine (SP) in West Africa, the effectiveness of dihydroartemisinin-piperaquine (DHA + PQ) was assessed as an alternative drug regimen for Seasonal Malaria Chemoprevention (SMC). This study aims to determine the prevalence of molecular markers of resistance to SP + AQ and DHA + PQ in Koulikoro (Mali), where SMC has been implemented since 2014. <i>Plasmodium falciparum</i>-positive samples were analyzed by either next-generation sequencing, focusing on SNPs in genes known to be associated with resistance: <i>Pfmdr1, PfK13, Pfcrt, Pfdhfr, Pfdhps,</i> and <i>Pfexo</i> genes, and using qPCR for copy number variations (CNVs) of <i>Pfmdr1</i> and <i>Pfplasmepsin2</i>. A total of 564 PCR-positive <i>P. falciparum</i> samples were analyzed: 218 in 2019 and 346 in 2020. In both years, the <i>Pfdhfr</i> <b>51I-59R-108N</b> haplotype was highly prevalent (>93%). In both arms, the <i>Pfdhps</i> single mutant (<b>437G</b>) was the most prevalent (~60%). In 2020, the combined haplotype <i>Pfdhfr/Pfdhps</i> <b>IRN/</b>IA<b>G</b>KA<b>S</b> and <b>IRN/V</b>A<b>G</b>K<b>GS</b> was detected at 9.6% and 1.2%, respectively. The <i>Pfmdr1</i> haplotype (N86-<b>F184</b>-S1034-N1042-D1246) represented more than 52.0%, and no difference was observed between the years, while a significant increase in the <i>Pfcrt</i> wild-type haplotype (C72-V73-M74-N75-K76) from 39% in 2019 to 52% in 2020 (<i>P</i> = 0.01) was observed. Some <i>PfK13</i> non-synonymous mutations were observed in both years, including Y<b>493H</b> and C<b>580R</b>. The identification of the <b>IRN</b>I<b>/</b>IA<b>G</b>KA<b>S</b> quintuple mutant, along with emerging <i>Pfdhps</i><b>-431V</b> and non-synonymous PfK13-<b>Y493H</b> variants, underscores the importance of continued surveillance of resistance markers.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0180624"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871020","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":"Colistin resistance dynamics in <i>Pseudomonas aeruginosa</i> under biofilm and planktonic growth.","authors":"Angie C Alarcon Rios, Laura B Zwep, Bastienne Vriesendorp, Catherijne A J Knibbe, Oana Ciofu, Apostolos Liakopoulos, Linda B S Aulin, Daniel E Rozen, J G Coen van Hasselt","doi":"10.1128/aac.00421-25","DOIUrl":"10.1128/aac.00421-25","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a major pathogen in chronic biofilm-associated lung infections, particularly in patients with cystic fibrosis. Colistin is commonly used to treat these infections, although there is little understanding of how resistance evolves when cells are grown within biofilms. The current study compared the phenotypic dynamics and genetic adaptations of colistin resistance between planktonic and biofilm-grown <i>P. aeruginosa</i>. Using an <i>in vitro</i> experimental evolution approach, we passaged planktonic and biofilm cultures over 10 days under static or progressively increasing colistin concentrations. Population analysis profiling was performed daily to track resistance dynamics and heterogeneity. Whole-genome sequencing was conducted on evolved lineages. Biofilm-grown populations exhibited significantly slower resistance rates than planktonic cultures, particularly under treatments above 0.5 mg/L (1×MIC). Despite this initial delay, both biofilm- and planktonic cultures ultimately evolved similar frequencies of resistant subpopulations. Genetically, we observed shared mutations in canonical colistin resistance determinants such as <i>phoQ</i> and <i>qseC</i>. We also identified growth-mode-specific patterns: <i>oprH</i> mutations were primarily found in biofilm-evolved populations, while <i>nfeD</i> mutations were pervasive in planktonic cultures but rare in biofilms. Taken together, our results provide key insights into the role of biofilm in shaping the evolutionary trajectories of colistin resistance evolution in <i>P. aeruginosa</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0042125"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940052","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":"Allelopathic compound 2-methoxy-1,4-naphthoquinone is broadly effective against pathogenic <i>Prototheca</i> species <i>in vitro</i> and <i>in vivo</i>.","authors":"Amir Aliramezani, Grzegorz Szewczyk, Krystian Mokrzyński, Izabela Ciastoń, Beatrycze Nowicka, Jakub M Kwiecinski","doi":"10.1128/aac.00497-25","DOIUrl":"10.1128/aac.00497-25","url":null,"abstract":"<p><p>Unpigmented, yeast-like <i>Prototheca</i> algae are emerging pathogens responsible for unusual infections in humans and animals. Their treatment is often unsuccessful, as traditional antifungals and antibacterials show unsatisfactory activity against <i>Prototheca</i>. Therefore, the development of improved drugs that consider the peculiarities of algal biology is needed. Here, we describe a novel anti-<i>Prototheca</i> compound, the 2-methoxy-1,4-naphthoquinone, identified among molecules known to mediate plant and algal allelopathy. The 2-methoxy-1,4-naphthoquinone was highly active <i>in vitro</i> against a range of <i>Prototheca</i> isolates from different species, both planktonically and in biofilms. Its mode of action included the induction of toxic reactive oxygen species, and it targeted energy generation in the pathogen's mitochondria. It effectively treated <i>Prototheca bovis</i> skin infection in a mouse model, demonstrating translational potential. Altogether, this study not only identified a new effective anti-<i>Prototheca</i> compound, but also identified 1,4-naphthoquinone backbone as a lead structure for further therapeutic development and demonstrated the feasibility of exploring known anti-plant compounds as a source of anti-<i>Prototheca</i> treatments.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0049725"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940062","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":"Fostemsavir analog BMS-818251 has enhanced viral neutralization potency and similar escape mutation profile.","authors":"Yen-Ting Lai, Adam S Dingens, Megan DeMouth, Sabrina Helmold Hait, Sijy O'Dell, Arne Schon, Adam S Olia, Tao Wang, Hannah R Shrader, Sarah E Lovelace, Amarendra Pegu, Nicole A Doria-Rose, John R Mascola, Jesse D Bloom, Peter D Kwong","doi":"10.1128/aac.01910-24","DOIUrl":"10.1128/aac.01910-24","url":null,"abstract":"<p><p>BMS-818251, a fostemsavir analog, is a next-generation HIV-1 attachment inhibitor with enhanced potency and a similar resistance profile. By using <i>ex vivo</i> viral outgrowth assays with HIV+ donor samples, we demonstrate here that BMS-818251 exhibits superior viral suppression compared to temsavir, the active form of fostemsavir. To map potential resistance pathways, we employed deep mutational scanning and pseudotyped virus neutralization assays to identify escape mutations within the HIV-1 envelope glycoprotein (Env). These mutations were largely clustered around the BMS-818251 binding site, with key resistance mutations reducing drug-binding affinity. Several of the enriched mutations, such as S375I/N, M426L, and M475I, have been previously observed in fostemsavir-treated patients, highlighting their clinical relevance. Isothermal titration calorimetry revealed reduced binding affinity as the primary mechanism of resistance, though with notable exceptions, such as R429G, suggesting additional factors to influence viral escape. <i>Ex vivo</i> Env sequencing confirmed selection of resistance mutations under BMS-818251 pressure, reinforcing the predictive value of deep mutational scanning for <i>in vivo</i> resistance monitoring. Compared to fostemsavir, BMS-818251 achieved more effective viral suppression at lower concentrations, even in donor samples harboring preexisting resistance mutations. These findings support the continued development of BMS-818251 as a promising alternative to fostemsavir, with potential benefits for patients with multidrug-resistant HIV-1.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0191024"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940108","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":"Evaluation of cycloserine dose regimens in an Indian cohort with multidrug-resistant tuberculosis: a population pharmacokinetic analysis.","authors":"Juan Eduardo Resendiz-Galvan, Prerna R Arora, Rohan V Lokhande, Zarir F Udwadia, Camilla Rodrigues, Amita Gupta, Jeffrey A Tornheim, Paolo Denti, Tester F Ashavaid","doi":"10.1128/aac.00101-25","DOIUrl":"10.1128/aac.00101-25","url":null,"abstract":"<p><p>Cycloserine is recommended for inclusion in regimens for multidrug-resistant tuberculosis (MDR-TB). Its efficacy is time dependent and relies on the concentration remaining above the minimum inhibitory concentration (MIC); however, there is a concentration-dependent risk of neurotoxicity. Limited pharmacokinetic (PK) data are available in individuals of Indian origin, despite the high burden of MDR-TB in India. We enrolled adults and adolescents receiving cycloserine for MDR-TB at a tertiary hospital in Mumbai, India, in a prospective cohort. Total daily doses ranged from 500 to 750 mg, and participants underwent serial PK sampling on multiple visits starting 1 month after treatment initiation. PK data were analyzed using non-linear mixed-effect modeling. A total of 180 participants (117 females) were enrolled, with a median age of 27 years (interquartile range [IQR] 21-35), weight of 56.0 kg (IQR 46.0-65.9), and fat-free mass of 38.6 kg (IQR 32.3-47.1). Cycloserine PK was best described by a one-compartment model with first-order elimination and transit compartment absorption. Allometric scaling by fat-free mass provided the best adjusment for body size. Serum creatinine improved the model fit and allowed separate estimation of renal and non-renal clearances, whose typical values were 0.589 and 0.901 L/h, respectively. Simulations showed median exposure of 308 mg·h/L after 250 mg twice daily (BID), which is lower than reported in literature. Monte Carlo simulations suggested that doses of 500 or 750 mg BID are required to reach efficacy targets of ≥30% and ≥64% time within dose interval above MIC. The reasons behind the low exposure identified in this Indian population require further investigation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0010125"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940154","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":"Lineage-specific evolution and resistance-virulence divergence in <i>Klebsiella pneumoniae</i> ST268: a global population genomic analysis.","authors":"Xu Dong, Yanghui Xiang, Yi Li, Ying Zhang","doi":"10.1128/aac.00703-25","DOIUrl":"10.1128/aac.00703-25","url":null,"abstract":"<p><p><i>Klebsiella pneumoniae</i> sequence type 268 (ST268) represents an emerging high-risk clone with significant clinical implications. Here, we present a comprehensive genomic analysis of 562 ST268 isolates collected from 44 countries across six continents between 2001 and 2024. Phylogenomic reconstruction revealed 10 distinct lineages with diverse geographic and functional signatures. Bayesian analysis dated the emergence of ST268 to ~1,908 (95% confidence interval [CI]: 1,841-1,952), with Europe as the likely origin. Our findings uncovered a clear evolutionary split between hypervirulent and multidrug-resistant subclones. Lineages L1 and L3 were enriched for carbapenemase genes (66.1% and 60%) and acquired genes involved in inorganic ion transport and amino acid metabolism, while L2 and L6 showed preferential carriage of hypervirulence markers and gene acquisitions related to secretion systems. Plasmid profiling revealed distinct virulence and resistance plasmid populations, with notable co-occurrence in 48 isolates predominantly from lineages L2 and L6, yet minimal integration between these elements. Nonsynonymous single-nucleotide polymorphisms further revealed lineage-specific functional variations, potentially driven by distinct ecological pressures. Phenotypic validation in <i>Galleria mellonella</i> and mouse models confirmed the high virulence of L2 and L6 strains. These patterns suggest a functional trade-off between resistance and virulence among ST268 lineages, likely shaped by parallel evolution under selective constraints. Our study provides novel insights into the genomic architecture and adaptive divergence of ST268, highlighting the need for lineage-informed surveillance and intervention strategies to mitigate its ongoing global dissemination.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0070325"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063392","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}