International Journal of Antimicrobial Agents最新文献

{"title":"\"Seesaw effect\" between daptomycin and ceftobiprole in daptomycin-resistant methicillin-resistant staphylococcus aureus isolates.","authors":"Mengzhen Chen, Shengnan Jiang, Lu Sun, Haiping Wang, Lingfang Di, Yeqiong Liu, Ying Zhang, Hemu Zhuang, Yueqin Hong, Zhengan Wang, Feiteng Zhu, Yiyi Chen, Shujuan Ji, Yunsong Yu, Yan Chen, Xiaoxing Du","doi":"10.1016/j.ijantimicag.2025.107469","DOIUrl":"https://doi.org/10.1016/j.ijantimicag.2025.107469","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to investigate the \"seesaw effect\" of daptomycin (DAP) and ceftobiprole (BPR) on DAP-resistant (DAP-R) methicillin-resistant Staphylococcus aureus (MRSA) isolates.</p><p><strong>Methods: </strong>Broth microdilution minimum inhibitory concentrations (MICs) of DAP and BPR were tested for laboratory-derived and clinical DAP-R MRSA isolates to estimate the \"seesaw effect\". Time-kill curves for seven representative DAP-R isolates were obtained using DAP and BPR to validate their synergistic activity in vitro. Whole genome sequencing as well as deletion and complementation of the mprF gene were performed to investigate the mechanisms of the \"seesaw effect\".</p><p><strong>Results: </strong>The BPR MICs decreased by half-fold in DAP-R MRSA isolates. The synergistic effect of DAP and BPR against representative clinical and community-associated MRSA (CA-MRSA) isolates was demonstrated in time-kill analyses, showing that synergistic activity was preferred in CA-MRSA compared with hospital-associated MRSA. The mprF mutations were identified in isolates exhibiting the \"seesaw effect\". These mutations increased the DAP MIC while decreasing the BPR MIC.</p><p><strong>Conclusions: </strong>The \"seesaw effect\" between DAP and BPR was prevalent among DAP-R MRSA isolates. This phenomenon was associated with the mprF mutations of MRSA.</p>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":" ","pages":"107469"},"PeriodicalIF":4.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476571","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":"The evolution of carbapenem-resistant Pseudomonas aeruginosa in the COVID-19 era: A global perspective and regional insights","authors":"Yan Li ,&nbsp;Xu Liu ,&nbsp;Hong Yao ,&nbsp;XiaoYu Zhao ,&nbsp;Leizi Chi ,&nbsp;Cheng Yun Jin ,&nbsp;Shangshang Qin","doi":"10.1016/j.ijantimicag.2025.107466","DOIUrl":"10.1016/j.ijantimicag.2025.107466","url":null,"abstract":"<div><h3>Objective</h3><div>Carbapenem-resistant <em>Pseudomonas aeruginosa</em> (CRPA) is a major contributor to healthcare-associated infections globally. The aim of this study was the impact of the COVID-19 pandemic on the genomic characteristics of <em>P. aeruginosa</em>, particularly clinical CRPA isolates.</div></div><div><h3>Methods</h3><div>Clinical data of each patient were collected from the clinical and medical record system. Whole-genome sequencing and bioinformatics analyses were performed to characterize the antibiotic resistance genes (ARGs) and evolutionary dynamics of these isolates. Furthermore, big data analysis was employed to elucidate the genomic characteristics of <em>P. aeruginosa</em> genomes across different periods on a global scale. Statistical analyses were applied to ensure the reliability of the findings.</div></div><div><h3>Results</h3><div>A total of 628 non-duplicate CRPA isolates were collected, with 256 isolates from before the COVID-19 pandemic and 372 during the pandemic. Only 26.59% of isolates carried carbapenemases, predominantly GES-14, and carbapenemase diversity decreased during the pandemic. However, the diversity of CRPA sequence types (STs) increased, with ST235 and ST244 emerging as the most prevalent clones. The Antibiotic resistance genes (ARGs) number carried by CRPA isolates significantly decreased during the pandemic (P &lt; 0.05), with notable differences in 24 ARGs and 14 virulence factors (VFs) between prepandemic and pandemic periods (<em>χ</em>² test, P &lt; 0.05). O11 was the predominant serotype across all periods. Global analysis revealed a significant reduction in ARGs in strains from China and Australia (P &lt; 0.01) during the pandemic. Analysis of the global epidemic clones ST244 and ST235 indicated that ARGs in ST244 <em>P. aeruginosa</em> increased significantly during the pandemic.</div></div><div><h3>Conclusions</h3><div>Our study highlights the critical need for ongoing surveillance of the evolutionary effects of the COVID-19 pandemic on clinical CRPA isolates, offering an essential theoretical basis for the development of effective and rational control strategies in clinical settings.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 5","pages":"Article 107466"},"PeriodicalIF":4.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457676","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":"Cefiderocol pharmacokinetics in critically-ill patients receiving extra-corporeal membrane oxygenation (ECMO)","authors":"Christina Koenig ,&nbsp;Andrew J. Fratoni ,&nbsp;Yasmeen Abouelhassan ,&nbsp;Jason A. Gluck ,&nbsp;David P. Nicolau ,&nbsp;Joseph L. Kuti","doi":"10.1016/j.ijantimicag.2025.107465","DOIUrl":"10.1016/j.ijantimicag.2025.107465","url":null,"abstract":"<div><h3>Objective</h3><div>Critical illness and organ support such as extracorporeal membrane oxygenation (ECMO) may influence antimicrobial pharmacokinetics. This study investigated cefiderocol pharmacokinetics in critically-ill patients receiving ECMO to understand if standard dosing achieves optimal exposure.</div></div><div><h3>Methods</h3><div>Cefiderocol was prescribed according to approved package insert recommendations based on creatinine clearance (CL). Blood sampling was performed at steady-state. Protein binding was determined by ultrafiltration. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. The <em>f</em>T &gt; MIC for each patient was assessed at MICs of 4, 8, and 16 mg/L. Total AUC_24h was calculated to evaluate comparative exposure to non-ECMO patients.</div></div><div><h3>Results</h3><div>Five patients receiving 1.5 g q8h to 2 g q6h dosing regimens were enrolled. Three patients received venous-arterial and two veno-venous ECMO (mean flow rate of 3.9 [range: 2.7–4.9] L/min). A two-compartment model fitted the data best with mean ± standard deviation estimates for CL, volume of the central compartment (V), K₁₂, and K₂₁ of 2.3 ± 0.5 L/h, 4.8 ± 2.3 L, 5.1 ± 2.8 h^–1, and 3.9 ± 3.3 h^–1, respectively. Mean protein binding was 41% (range: 31%–50%). Prescribed dosing regimens achieved 100% <em>f</em>T &gt; MIC up to 16 mg/L for all patients, with a total steady-state AUC_24h of 2501 (range: 1631–3276) mg/L·h.</div></div><div><h3>Conclusions</h3><div>These are the first data to describe cefiderocol pharmacokinetics in critically-ill patients undergoing ECMO. The currently labelled dosing recommendations based on creatinine CL in these patients were well tolerated and achieved 100% <em>f</em>T &gt; MIC against susceptible bacteria and AUC exposures similar to values in non-ECMO patients.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 5","pages":"Article 107465"},"PeriodicalIF":4.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457644","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":"Potential therapeutic substances for hand-foot-and-mouth disease in the interplay of enteroviruses and type I interferon","authors":"Xinyu Wang ,&nbsp;Ziyuan Wang ,&nbsp;Zhongtian Qi ,&nbsp;Yongzhe Zhu","doi":"10.1016/j.ijantimicag.2025.107464","DOIUrl":"10.1016/j.ijantimicag.2025.107464","url":null,"abstract":"<div><h3>Objectives</h3><div>Hand-foot-and-mouth disease (HFMD) is widespread in the world. Severe HFMD can lead to complications like pneumonia, encephalitis, myocarditis, transverse myelitis and even death. Since HFMD is caused by at least 20 types of enteroviruses, there is an urgent need for broad-spectrum antiviral drugs to help control the spread of HFMD outbreaks.</div></div><div><h3>Methods</h3><div>Type I interferon (IFN), as an indispensable part of the immune response, plays a key role in the inhibition of the enterovirus replication cycle without species specificity, and regulation of the innate immune system by inducing the activation of the IFN-stimulated genes.</div></div><div><h3>Conclusions</h3><div>Here, the interplay of enteroviruses and type I IFN was systematically summarized, including pathways for the activation and evasion of type I IFN. Besides, we proposed promising anti-enterovirus agents with therapeutic potential.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 5","pages":"Article 107464"},"PeriodicalIF":4.9,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of carbapenem-resistant Citrobacter spp. across human, animal, and water environments in China.","authors":"Xiaoyang Ju, Panfeng Xiong, Zelin Yan, Gongxiang Chen, Chang Cai, Rong Zhang","doi":"10.1016/j.ijantimicag.2025.107463","DOIUrl":"https://doi.org/10.1016/j.ijantimicag.2025.107463","url":null,"abstract":"<p><p>Recently, the number of carbapenem-resistant Citrobacter spp.(CRC) have been on the rise. In this study, we collected CRCs from humans, animals, and water environments to examine their epidemiological distribution and resistance characteristics. Total of 171 CRCs were isolated from diverse Chinese provinces between 2016 and 2023. All strains are classified into seven Citrobacter species, C. freundii is the most common (76.02%), with ST116 and ST22 being the predominant strains. Among all strains, 63.16% carried bla_NDM-1, and 41.52% carried bla_KPC-2. Hospital wastewater was the primary source of CRCs harboring two carbapenemase genes, with the most prevalent combination being bla_NDM-1 and bla_KPC-2 (85.71%, 24/28). All strains showed multiple drug resistance, with over 95% resistant to various carbapenems. Transconjugation experiments showed that carbapenemase genes in the majority of CRCs were located on the plasmids and can be transferred to the recipient strains. According to the phylogenetic analysis, clonal transmission was observed among a few CRCs. Multiple mobile genetic elements mediate the spread and prevalence of carbapenem resistance in Citrobacter spp..</p>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":" ","pages":"107463"},"PeriodicalIF":4.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425344","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":"Ceftriaxone population pharmacokinetics in plasma and cerebrospinal fluid of neurocritical care patients","authors":"Nilesh Kumta ,&nbsp;Aaron J. Heffernan ,&nbsp;Xin Liu ,&nbsp;Suzanne L. Parker ,&nbsp;Menino Osbert Cotta ,&nbsp;Steven C. Wallis ,&nbsp;Amelia Livermore ,&nbsp;Therese Starr ,&nbsp;Wong Tat Wai ,&nbsp;Gavin M. Joynt ,&nbsp;Jeffrey Lipman ,&nbsp;Jason A. Roberts","doi":"10.1016/j.ijantimicag.2025.107461","DOIUrl":"10.1016/j.ijantimicag.2025.107461","url":null,"abstract":"<div><h3>Background</h3><div>Patient outcomes during ventriculitis may be improved by antibiotic dose optimisation strategies that increase the achievement of therapeutic concentrations at the infection site. We performed a population pharmacokinetic (PK) study in neurocritical care patients to define ceftriaxone dosing regimens required to achieve effective cerebrospinal fluid (CSF) exposures.</div></div><div><h3>Methods</h3><div>Patients receiving ceftriaxone for treatment of ventriculitis or extracerebral infections or for prophylaxis following external ventricular drain insertion were recruited and subject to serial plasma and CSF sampling. Population PK modeling and dosing simulations to achieve the following plasma targets: (a) unbound ceftriaxone concentration above pathogen minimum inhibitory concentration over the dosing interval (100% <em>f</em>T_&gt;MIC) and (b) unbound ceftriaxone concentration at least fourfold above pathogen minimum inhibitory concentration over the dosing interval (100% <em>f</em>T_&gt;4×MIC), were performed.</div></div><div><h3>Results</h3><div>Ten patients were recruited; median age, weight, and creatinine clearance were 57 years, 60 kg, and 107 mL/min/1.73m², respectively. Ceftriaxone PK displayed considerable variability, especially in CSF, with between subject variability ranging from 21% to 794%. Median total ceftriaxone CSF penetration was 1.43% (range 0.33–8.42). Intermittent infusions of 2 g every 8 hours achieved 99.5% and 82% probability of attaining 100% <em>f</em>T_&gt;MIC and <em>f</em>T_&gt;4×MIC in plasma for an MIC of 1 mg/L, respectively. The model was unable to accurately predict ceftriaxone concentrations in CSF, precluding CSF dosing simulations.</div></div><div><h3>Conclusions</h3><div>High attainment of plasma target exposures was achieved with higher than standard dosing. Dosing recommendations to optimise targeted CSF ceftriaxone exposures for treatment of ventriculitis could not be made given inadequate model predictability.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 5","pages":"Article 107461"},"PeriodicalIF":4.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382007","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":"International Society of Antimicrobial Chemotherapy (ISAC) News and Information Page","authors":"","doi":"10.1016/j.ijantimicag.2025.107462","DOIUrl":"10.1016/j.ijantimicag.2025.107462","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 3","pages":"Article 107462"},"PeriodicalIF":4.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143193779","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":"Development and validation of a time-varying correction factor for QT interval assessment in drug-resistant tuberculosis patients","authors":"Thanakorn Vongjarudech ,&nbsp;Anne-Gaëlle Dosne ,&nbsp;Bart Remmerie ,&nbsp;Kelly E. Dooley ,&nbsp;James C.M. Brust ,&nbsp;Gary Maartens ,&nbsp;Graeme Meintjes ,&nbsp;Mats O. Karlsson ,&nbsp;Elin M. Svensson","doi":"10.1016/j.ijantimicag.2025.107460","DOIUrl":"10.1016/j.ijantimicag.2025.107460","url":null,"abstract":"<div><h3>Background</h3><div>Tachycardia associated with active tuberculosis (TB) often diminishes when patients recover from TB. Elevated heart rate (HR) may lead to suboptimal correction, complicating the assessment of QT prolongation when using standard correction factors (CFs), such as Fridericia's formula (QTcF). Olliaro has proposed a CF for QT interval correction in pretreatment TB patients. However, the QT-HR correlation changes as HR decreases during treatment, indicating the need for time-varying correction.</div></div><div><h3>Methods</h3><div>We developed an HR model to capture the HR normalisation during successful treatment. Subsequently, a time-varying CF was constructed using the estimated HR change rate. The performance of CFs to make corrected QT (QTc) independent from HR was evaluated by linear regression analyses of QTc versus HR within defined time bins.</div></div><div><h3>Results</h3><div>The final HR model included asymptotic change in HR attributed to time on treatment, circadian rhythm cycles, M2 (bedaquiline-metabolite) concentration, and patient covariates. The time-varying CF decreased from 0.4081 to 0.33, with a half-life of 7.74 weeks. The slope (QTc/HR vs. Time) derived from the time-varying correction was not significantly different from 0 (95% CI –0.003 to 0.002), and the intercept was not significantly different from 0 (95% CI –0.089 to 0.006), demonstrating successful QT correction from pretreatment to the end of treatment.</div></div><div><h3>Conclusion</h3><div>The time-varying CF effectively captures the dynamic QT-HR relationship during TB treatment, reducing the risk of misdiagnosing QT prolongation or unnecessary discontinuation of treatment. By addressing underestimation and overestimation issues in QT interval assessment, this method enhances drug evaluation in clinical trials and supports improved treatment decisions for TB patients.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 4","pages":"Article 107460"},"PeriodicalIF":4.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373962","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":"Transgenerational gut dysbiosis: Unveiling the dynamics of antibiotic resistance through mobile genetic elements from mothers to infants","authors":"Samiya Farooq ,&nbsp;Absar Talat ,&nbsp;Achal Dhariwal ,&nbsp;Fernanda Cristina Petersen ,&nbsp;Asad U. Khan","doi":"10.1016/j.ijantimicag.2025.107458","DOIUrl":"10.1016/j.ijantimicag.2025.107458","url":null,"abstract":"<div><h3>Objectives</h3><div>The initial microbial colonization of the gut is seeded by microbes transmitted from the mother's gut, skin, and vaginal tract. As the gut microbiome evolves, a few transmitted microbes persist throughout life. Understanding the impact of mother-to-neonate gut microbiome and antibiotic resistance genes (ARGs) transmission is crucial for establishing its role in infants' immunity against pathogens.</div></div><div><h3>Methods</h3><div>This study primarily explores mother-neonate ARG transmission through 125 publicly available fecal metagenomes, isolated from eighteen mother-neonate pairs.</div></div><div><h3>Results</h3><div>The core ARGs, detected in both mothers and their respective infants at all stages (birth, 1st, 2nd, 3rd, 4th, 8th and 12th months) included aminoglycosidases <em>APH(3′)-</em>IIIa, <em>Bifidobacterium adolescentis rpoB</em> mutants conferring resistance to rifampicin, β-lactamases <em>CblA-1, CfxA2</em>, multidrug resistance gene <em>CRP,</em> diaminopyrimidine resistance gene <em>dfrF</em>, fluoroquinolone-resistance gene <em>emrR</em>, macrolide; lincosamide; streptogramin resistance gene <em>ErmB, ErmG</em>, macrolide resistance gene <em>Mef(En2)</em>, nucleosidase <em>SAT-4</em>, and tetracycline-resistance genes <em>tet(O), tet(Q)</em>, and <em>tet(W).</em> Most of these infants and mothers were not administered any antibiotics. In infants, ARGs were predominantly carried by Bacillota, Pseudomonadota, and Actinomycetota, similar to the mothers. The dominant ARG-carrying opportunistic pathogens were <em>Escherichia coli, Klebsiella</em>, and <em>Streptococcus</em>, found across all infant cohorts. All the core ARGs were associated with mobile genetic elements, signifying the role of horizontal gene transfer(HGT). We detected 132 virulence determinants, mostly <em>E. coli</em>-specific, including pilus chaperones, general secretion pathway proteins, type III secretion system effectors, and heme-binding proteins.</div></div><div><h3>Conclusions</h3><div>Maternal-neonate transmission of ARGs along with possible nosocomial infections, mode of delivery, breastfeeding versus formula feeding, and gestation period, must be considered for mother-neonate health.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 5","pages":"Article 107458"},"PeriodicalIF":4.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373965","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":"Subminimum inhibitory concentrations of rifampicin attenuate methicillin-resistant staphylococcus aureus virulence by suppressing SaeRS two-component system and arginine metabolism-related pathways","authors":"Yanghua Xiao ,&nbsp;Yanlei Xu ,&nbsp;Weihua Han ,&nbsp;Bingjie Wang ,&nbsp;Fangyou Yu","doi":"10.1016/j.ijantimicag.2025.107459","DOIUrl":"10.1016/j.ijantimicag.2025.107459","url":null,"abstract":"<div><h3>Objectives</h3><div>Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) poses a significant threat to global public health, prompting the exploration of alternative strategies to mitigate its virulence. This study investigates the impact of subminimum inhibitory concentrations (sub-MICs) of rifampicin on MRSA virulence, aiming to provide insights for optimizing antibiotic treatment strategies.</div></div><div><h3>Methods</h3><div>Enzyme-linked immunosorbent assay and western blot analysis were used to assess α-hemolysin expression. Transcriptomic sequencing and RT-qPCR analyzed gene expression changes in MRSA treated with sub-MICs of rifampicin. Mutant strains (Δ<em>saeR</em> and Δ<em>argGH</em>) were constructed to validate the roles of the SaeRS system and arginine metabolism. Thermal shift assays evaluated the interaction between L-arginine and SaeR protein. <em>In vivo</em> murine models and <em>Galleria mellonella</em> infection models were used to assess the anti-virulence effects of rifampicin.</div></div><div><h3>Results</h3><div>Our findings reveal that sub-MICs of rifampicin significantly reduce the expression of MRSA α-hemolysin. Transcriptomic sequencing and RT-qPCR analysis suggest a dual-pathway mechanism, wherein rifampicin suppresses virulence by indirectly inhibiting the SaeRS two-component system and disrupting arginine metabolism-related pathways. The construction of a <em>saeR</em> knockout mutant (Δ<em>saeR</em>) and an arginine biosynthesis deficient mutant (Δ<em>argGH</em>) further supports this mechanism. Notably, exogenous <span>l</span>-arginine supplementation reverses rifampicin's inhibitory effect on α-hemolysin expression, underscoring the pivotal role of <span>l</span>-arginine metabolism in MRSA virulence regulation. Thermal shift assays demonstrate a direct interaction between <span>l</span>-arginine and SaeR protein, elucidating the intricate interplay between metabolic pathways and virulence regulation. <em>In vivo</em> studies confirm that sub-MICs of rifampicin attenuate the severity of skin abscesses in a murine model, improve survival rates in bloodstream infection models, and mitigate inflammation in both skin and lung tissues.</div></div><div><h3>Conclusion</h3><div>This study highlights the potential of rifampicin as an anti-virulence agent and pave the way for the development of innovative therapeutic strategies targeting MRSA infections.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 4","pages":"Article 107459"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254436","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}