Antimicrobial Agents and Chemotherapy最新文献

{"title":"Model-informed drug development in public health emergency of international concern: accelerating marketing authorization of simnotrelvir.","authors":"Bu-Fan Yao, Yang Yang, Shan-Sen Xu, Bo-Hao Tang, Jia Chen, Zi-Jia Guo, Hong-Lin Hu, Wei Zhang, Shu-Meng Fu, Xin-Fang Zhang, Guo-Xiang Hao, Xin-Mei Yang, Lin-Lin Song, Pan-Pan Ye, Lian Liu, Shun-Wei Zhu, Yi Zheng, Wei Zhao","doi":"10.1128/aac.00614-25","DOIUrl":"https://doi.org/10.1128/aac.00614-25","url":null,"abstract":"<p><p>During a Public Health Emergency of International Concern (PHEIC), rapid drug development is critical, but traditional clinical trials are time-consuming and high-risk. This study used coronavirus disease 2019 (COVID-19) as an example to highlight the pivotal role of model-informed drug development (MIDD) in expediting the marketing authorization of simnotrelvir in China, a 3CL^pro inhibitor for COVID-19 treatment. Three simnotrelvir clinical trials (Phase Ia, Ib, II/III) were optimized using the MIDD approach. Pharmacokinetics was investigated using nonlinear mixed-effects models, exposure was calculated through Monte Carlo simulation and Bayes estimation, and exposure-efficacy/safety relationships were analyzed using linear/logistic regression models. The MIDD approach began with a translational study to predict patients' starting doses using first-in-human data, preclinical data, and pharmacodynamic surrogate marker. A dose level of 750 mg/100 mg simnotrelvir/ritonavir was recommended, using simulation results with 90.6% of participants' trough concentration exceeding EC₉₀ for anti-Omicron variant. Then, a biomarker confirmation study to investigate dose-exposure-response relationship found that 750 mg suppressed viral load more than 300 mg (-4.995 vs. -4.236 log₁₀ copies/mL, <i>P</i> = 0.0367) in Phase Ib. Finally, a randomized controlled trial to confirm benefit-risk ratio found that simnotrelvir/ritonavir reduced time to sustained resolution of 11 clinical syndromes by 1.5 days compared with placebo, had no serious adverse events, and had a flat exposure-response relationship with viral load reduction, time to sustained resolution, and ≥2 grade treatment-emergent adverse event rate with approved dosage. MIDD enhanced clinical trial success, optimized the benefit-risk profile, and expedited marketing authorization for new drug development in response to PHEIC.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05339646, NCT05369676, and NCT05506176.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0061425"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079493","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":"Comparison of early treatment with ceftolozane/tazobactam versus polymyxin-based therapy of pneumonia due to MDR <i>Pseudomonas</i> <i>aeruginosa</i> (PUMA).","authors":"Thomas P Lodise, Jae Min, Brian H Nathanson, Emre Yücel","doi":"10.1128/aac.00569-25","DOIUrl":"https://doi.org/10.1128/aac.00569-25","url":null,"abstract":"<p><p>Ceftolozane/tazobactam and polymyxin-based regimens are frequently used to treat pneumonia caused by multi-drug-resistant <i>P. aeruginosa</i> (MDR-PSA). However, comparative data on global clinical outcomes between these therapies are limited. A multi-centered observational study was performed using the PINC AI^TM Healthcare Database (2016-2022). The study population included hospitalized patients ≥ 18 years who were diagnosed with pneumonia and had MDR-PSA (defined as non-susceptible to ≥1 agent in ≥3 antimicrobial categories) on a respiratory or blood culture, receipt of ceftolozane/tazobactam or a polymyxin-based regimen within 3 days of index MDR-PSA culture, receipt of ≥2 days of ceftolozane/tazobactam or a polymyxin-based regimen, and without a COVID-19 diagnosis. A Desirability of Outcome Ranking (DOOR) analysis was performed. Components of the DOOR included in-hospital mortality, discharge destination (home vs other), recurrent MDR-PSA pneumonia, receipt of any renal replacement therapy (RRT) post-index culture in RRT-naive patients, and 30-day pneumonia-related readmissions. In total, 186 patients met the study criteria (104 ceftolozane/tazobactam and 82 polymyxin). In the IPW-adjusted DOOR analysis, a ceftolozane/tazobactam-treated patient had a higher probability of a more favorable outcome (DOOR probability: 61.3%; 95% CI: 56.8%, 65.7%). In the DOOR partial credit analyses, a ceftolozane/tazobactam-treated patient had a higher probability of being discharged home alive with no undesirable outcomes than a polymyxin-treated patient (20.2% vs 9.8%, <i>P</i> = 0.04). This real-world evidence study of non-COVID-19 patients with MDR-PSA pneumonia suggests that patients treated with ceftolozane/tazobactam have a higher probability of a more favorable outcome compared with patients treated with a polymyxin-based regimen. Further large-scale studies with detailed dosing are needed to validate the findings.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0056925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079515","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":"Biological cost of aminoglycoside resistance Arm/Kam 16S rRNA methyltransferases from natural antibiotic producers and clinical pathogens.","authors":"Darija Vidučić, Sonja Obranić, Mihaela Matovina, Fedora Babić, Gordana Maravić-Vlahoviček","doi":"10.1128/aac.00742-25","DOIUrl":"10.1128/aac.00742-25","url":null,"abstract":"<p><p>16S rRNA methyltransferases have emerged as critical elements of high-level aminoglycoside resistance in clinical pathogens. We investigated the fitness costs associated with the expression of six methyltransferases isolated from clinical strains (ArmA, RmtA, RmtB, RmtC, RmtD, and NpmA), and two methyltransferases from natural antibiotic producers (Sgm and KamB) in <i>Escherichia coli</i>. Growth competition assays revealed that methyltransferases found in natural producers imposed significantly lower fitness costs than those isolated from clinical strains, allowing resistant populations to persist at stable levels. Translational fidelity assays demonstrated that most methyltransferases induce error-prone phenotypes by allowing increased readthrough of nonsense codons and frameshift mutations, while KamB uniquely increased translational accuracy. Deletion of the housekeeping methyltransferase RsmF further altered these effects, highlighting the complex interplay between endogenous and exogenous methylation processes. Stress response experiments showed varying results: most methyltransferases increased susceptibility to hyperosmotic stress, while several (RmtB, RmtA, ArmA, and KamB) increased tolerance to acidic stress. These findings reveal that 16S rRNA methyltransferases play complex roles in bacterial physiology beyond antibiotic resistance, with important implications for the persistence of resistance and potential therapeutic strategies targeting specific vulnerabilities in resistant bacteria.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0074225"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752109","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":"Clinical pharmacokinetics of metronidazole: a systematic review and meta-analysis.","authors":"Iqra Shahzad, Mohammed S Alasmari, Ammara Zamir, Muhammad Fawad Rasool, Faleh Alqahtani","doi":"10.1128/aac.01904-24","DOIUrl":"10.1128/aac.01904-24","url":null,"abstract":"<p><p>Metronidazole (MTZ) is used in various clinical settings; however, its pharmacokinetics may vary across patient populations due to physiological and pathological differences. Understanding these variations is important for personalized dosing and optimization of therapeutic outcomes. This study aimed to systematically review clinical pharmacokinetic studies of MTZ and perform a meta-analysis of the area under the concentration-time curve (AUC). AUC was selected for meta-analysis as it provides a direct and comprehensive measure of total drug exposure over time, facilitating standardized comparisons across populations. Four databases, including PubMed, ScienceDirect, Cochrane Library, and Google Scholar, were screened for pharmacokinetic studies on MTZ using systematic search strategies until July 2024. Out of 1,882 articles identified in the literature search, only 67 studies that fulfilled eligibility criteria were included in this systematic review. A meta-analysis of AUC was performed using random-effects models, with heterogeneity assessed by <i>I</i>² statistic. Effect sizes (pooled AUC) were compared across populations and visually presented with their corresponding 95% confidence intervals. Meta-analysis revealed significant differences in AUC across populations, with substantial heterogeneity among studies. This study provides a comprehensive evaluation of the MTZ pharmacokinetic profile across diverse patient populations. The findings emphasize the importance of tailored dosing strategies and support evidence-based clinical decision-making for optimizing the safety and efficacy of MTZ.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0190424"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752110","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":"Assessment of human exposures of cefepime-taniborbactam against cefepime-resistant Enterobacterales and <i>Pseudomonas aeruginosa</i> in a 7-day hollow fiber infection model.","authors":"Lindsay M Avery, Mitchell Edwards, Fan Yi, Greg Moeck, Tsuyoshi Uehara, Daniel C Pevear","doi":"10.1128/aac.00017-25","DOIUrl":"10.1128/aac.00017-25","url":null,"abstract":"<p><p>Taniborbactam is a novel cyclic boronate β-lactamase inhibitor that potentiates the <i>in vitro</i> activity of cefepime against Enterobacterales and <i>Pseudomonas aeruginosa</i> strains harboring serine and metallo-β-lactamases. Taniborbactam lacks intrinsic antibacterial activity. An <i>in vitro</i> hollow fiber infection model (HFIM) was used to evaluate bacterial kill and the potential for treatment-emergent resistance associated with the clinical cefepime-taniborbactam dose of 2-0.5 g every 8 h, administered as a 2 h infusion, for 7 days. Nine cefepime-resistant bacterial strains were studied among one <i>Escherichia coli</i>, five <i>Klebsiella pneumoniae</i>, and three <i>P. aeruginosa</i> that harbored a variety of cephalosporinases, extended-spectrum β-lactamases, and carbapenemases with cefepime-taniborbactam MIC values that ranged from 0.25 to 8 µg/mL. All nine strains grew rapidly when treated with cefepime alone, consistent with phenotypic resistance. Human plasma concentration-time profiles for cefepime and taniborbactam were simulated in the HFIM systems and resulted in bactericidal activity (≥3 log₁₀ CFU/mL reduction) against eight of nine strains when assessed 8 h after initiation of the first dose, and against all nine strains by day 7. Treatment-emergent resistance, defined as bacterial subpopulations with ≥4 times the baseline MIC, was not detected in any cefepime-taniborbactam model from days 1 to 7. Therefore, human cefepime-taniborbactam exposures demonstrated sustained bactericidal activity and suppressed the emergence of resistance in a 7-day HFIM among serine and metallo-β-lactamase-positive Enterobacterales and <i>P. aeruginosa</i> strains. These observations support the clinical development of cefepime-taniborbactam and inform understanding of its potential role in treating serine and/or metallo-β-lactamase-positive Gram-negative bacterial infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0001725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752136","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":"Inhibition of efflux pumps by FDA-approved drugs oxiconazole and sertaconazole restores antibiotic susceptibility in multidrug-resistant <i>S. aureus</i>.","authors":"Suvendu Ojha, Puja Chatterjee, Tushar Kant Beuria","doi":"10.1128/aac.00320-25","DOIUrl":"10.1128/aac.00320-25","url":null,"abstract":"<p><p>Antibiotic resistance in <i>Staphylococcus aureus</i> causes major concern worldwide. In <i>S. aureus</i>, efflux pumps are mostly responsible for the development of multidrug resistance. Active removal of antibiotics from cells by <i>S. aureus</i> efflux pumps, including NorA, NorB, AbcA, and MepA, helps to lower their intracellular concentration and effectiveness. The present study examined two FDA-approved antifungal medications, oxiconazole and sertaconazole, as possible efflux pump inhibitors (EPIs) against multidrug-resistant <i>S. aureus</i>. Our results showed that both drugs reduced the efflux pump activity of drug-susceptible (ATCC25923) and multidrug-resistant (Mu50) <i>S. aureus</i> strains. While sertaconazole inhibited the efflux pumps without changing the efflux rate, oxiconazole lowered both efflux pump activity and efflux rate. Neither of these drugs impacted bacterial membrane integrity nor bacterial growth. Both drugs enhanced the efficacy of norfloxacin, cefotaxime, and moxifloxacin by lowering the MIC values and showed minimal cytotoxicity toward mammalian cells. In combination with the antibiotics, both sertaconazole and oxiconazole significantly lowered the bacterial load in a murine skin infection model. Our results suggested that the drugs altered the proton motive force (PMF), which resulted in diminished membrane potential (Δ<i>Ψ</i>) and an increased electrochemical gradient (ΔpH), thereby inhibiting ATP production and efflux pump activity. The safety profile and potential to enhance antibiotic efficacy suggest that sertaconazole and oxiconazole may be used as EPIs for combating multidrug-resistant <i>S. aureus</i> infections. Further studies are required to assess their pharmacokinetics, toxicity, and activity against a wide range of <i>S. aureus</i> isolates.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0032025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774582","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":"Amoxicillin vs. ceftriaxone to treat pneumonia caused by amoxicillin-non-susceptible <i>Streptococcus pneumoniae</i>.","authors":"Daniel M Musher","doi":"10.1128/aac.00780-25","DOIUrl":"10.1128/aac.00780-25","url":null,"abstract":"<p><p>Although the article by J Càmara, I Grau, A González-Díaz, N Santos, et al. (Antimicrob Agents Chemother 69:e00237-25, 2025, https://doi.org/10.1128/aac.00237-25) suggests that ceftriaxone is greatly superior to amoxicillin in treating pneumonia due to pneumococci with an MIC > 2 mg/L, much of the difference in efficacy of the two drugs may have been due to dosage, route, and times of administration of the amoxicillin.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0078025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833754","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":"Complementary killing activities of <i>Pbunavirus LS1</i> and <i>Bruynoghevirus LUZ24</i> phages on planktonic and sessile <i>Pseudomonas aeruginosa</i> PAO1 derivatives.","authors":"Maud Billaud, Clarisse Plantady, Benoît Lerouge, Emma Ollivier, Julien Lossouarn, Elisabeth Moncaut, Julien Deschamps, Romain Briandet, Aurore Cleret, Cindy Fevre, Gaëlle Demarre, Marie-Agnès Petit","doi":"10.1128/aac.00579-25","DOIUrl":"10.1128/aac.00579-25","url":null,"abstract":"<p><p>Four phages active against a representative panel of <i>Pseudomonas aeruginosa</i> strains were chosen with the goal of using them for phage therapy. Two were belonging to the <i>Pbunavirus LS1</i> species, and two to the <i>Bruynoghevirus LUZ24</i> species. The receptor of the <i>P. LS1</i> phage Ab27 had already been characterized as the O-antigen chain of the lipopolysaccharides, whereas no information was available at the onset of this work on the receptor used by the <i>B. LUZ24</i> phages. We show that this receptor is the surface polysaccharide Psl, an important component of the biofilm matrix. Remarkably, the <i>B. LUZ24</i> phages were more active against PAO1 in minimal medium compared to rich medium. This was correlated with larger amounts of Psl bound at the bacterial surface during exponential growth in minimal medium, compared to the rich medium. Phages prevented biofilm growth when applied early after biofilm formation on a medical endotracheal tube, as well as in 96-well plates, and acted more slowly on mature biofilms. No biofilm overgrowth was observed when applying the two phage species combination, over a 48 h period of imaging by confocal microscopy. Genetic mutants resistant to each phage arose at a frequency of 10^-5 to 10^-6 per generation, and most <i>P. LS1</i>-resistant mutants were sensitized to the <i>B. LUZ24</i> phage. The combination of the selected phages has promising properties that are relevant in the framework of phage therapy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0057925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688759","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":"Evolution of XDR <i>Pseudomonas aeruginosa</i> ST463 strains with two plasmids harboring multiple antimicrobial resistance genes.","authors":"Yinfei Fang, Meijun Song, Yisha Zhang, Zhaoxia Wu, Xiaobing Li, Yuxiang Guo, Nanfei Wang, Xiaoting Hua, Yunsong Yu","doi":"10.1128/aac.01697-24","DOIUrl":"10.1128/aac.01697-24","url":null,"abstract":"<p><p>The extensively drug-resistant (XDR) <i>Pseudomonas aeruginosa</i> ST463 strains, which co-harbor plasmid-associated metallo-β-lactamase (MBL) and <i>bla</i>_KPC-2 genes, exhibit significant resistance and virulence, posing great clinical treatment challenges. Here, we report on three XDR <i>P. aeruginosa</i> ST463 strains, PA64, PA3117, and PA30, all carrying two plasmid types. One plasmid was a ~450 kb IncP-2-type megaplasmid named pPA64_1, pPA3117_1, and pPA30_1 in strains PA64, PA3117, and PA30, respectively. The other plasmid was a type I plasmid named pPA64_2, pPA3117_2, and pPA30_2 in strains PA64, PA3117, and PA30, respectively, harboring the <i>bla</i>_KPC-2 gene in the core genetic platform IS<i>Kpn27- bla</i>_KPC-2-IS<i>Kpn6</i>. The <i>bla</i>_KPC-2 gene copies were associated with IS<i>26</i>-mediated inversion or duplication events. Notably, the IncP-2 megaplasmids pPA64_1, pPA3117_1, and pPA30_1 were associated with a variable ~57.3 kb Tn<i>1403</i>-like transposon named Tn<i>6485g</i>, Tn<i>6485h</i>, and Tn<i>6485f</i>, respectively. Tn<i>6485g</i> carried the MBL gene <i>bla</i>_IMP-45, which was located in the class 1 integron In<i>786</i>, followed by an IS<i>CR1</i>-associated <i>armA</i> module and the IS<i>26</i>-composite transposon Tn<i>6309</i>. On this basis, other IS<i>CR1</i>-associated modules (IS<i>CR1-qnrVC6</i>, IS<i>CR1-bla</i>_PER-1, and IS<i>CR1-bla</i>_AFM-1) were inserted between In<i>786</i> derivatives and IS<i>CR1-armA</i>, resulting in a novel transposon, Tn6<i>485h</i>, carrying two MBL genes, <i>bla</i>_IMP-45 and <i>bla</i>_AFM-1. In contrast to Tn6<i>485h</i>, Tn<i>6485f</i> had another inserted copy of IS<i>CR1-qnrVC6</i>. We inferred that the evolution of the Tn<i>1403</i>-like transposon might be driven by the recruitment of IS<i>CR1</i>-associated antimicrobial resistance (AMR) modules under antibiotic pressure in a clinical setting.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0169724"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688762","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":"Indolenine-substituted pyrazole derivative 4e inhibits planktonic <i>Staphylococcus lugdunensis</i> growth and biofilm formation by disrupting purine biosynthesis and compromising cell wall and membrane integrity.","authors":"Jazon Harl Hidrosollo, Hsiao-Wei Liao, Cheng Hong Yap, Jason Jonah James, Jang-Jih Lu, Yu-Hsien Tai, Chuancheng Wei, Tran Thi Dieu Thuy, Sek Peng Chin, Sun Tee Tay, Chin Fei Chee, Cheng Yen Kao","doi":"10.1128/aac.00199-25","DOIUrl":"10.1128/aac.00199-25","url":null,"abstract":"<p><p><i>Staphylococcus lugdunensis</i> is an emerging nosocomial pathogen responsible for biofilm-related infections. Here, we explored the antibacterial and antibiofilm properties of the novel indolenine derivative 4e against <i>S. lugdunensis</i> and investigated its mechanisms of action. Its antibacterial and antibiofilm activities were assessed against oxacillin-resistant <i>S. lugdunensis</i> CGMH-SL131 using <i>in vitro</i> and <i>in vivo</i> models, including human cell lines, <i>Galleria mellonella</i> larvae, and mice. Mechanistic insights were explored via untargeted metabolomics. 4e exhibited bacteriostatic activity against a panel of gram-positive bacteria, with a 1× minimum inhibitory concentration (MIC) of 62.5 µg/mL. Scanning electron microscope observations of cells treated with 0.5% SDS and 1× MIC 4e displayed signs of cell shape distortion, including complete shrinkage and bursting. 4e effectively inhibited biofilm formation by 54.3% at 1.56 µg/mL, and the minimum biofilm inhibition concentration 80% (MBIC₈₀) was 3.125 µg/mL. In addition, 70.3% of 1-day preformed biofilms were dispersed at 1× MBIC₈₀. 4e exhibited low cytotoxicity (>85% survival) in HaCaT, H10975, and Caco-2 cells at 1× MIC. When administered 1 hour post-infection, 4e (3.125 mg/kg) improved larval survival to 90%, matching tigecycline (2 mg/kg), whereas untreated larvae had only 20% survival after 7 days. In C57BL/6 mice, 4e (2.5 mg/kg) reduced kidney bacterial loads from 10⁷ to 5.3 × 10⁴ CFU. Untargeted metabolomics suggests that 4e's antibacterial and antibiofilm effects result from disrupting purine biosynthesis and compromising cell wall and membrane integrity. These findings highlight 4e as a promising new antibiofilm agent and potential alternative treatment for biofilm-related infections caused by <i>S. lugdunensis</i> and multidrug-resistant <i>Staphylococcus</i> species.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0019925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688763","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}