Antimicrobial Agents and Chemotherapy最新文献

{"title":"Genetic analysis of common triazole resistance mechanisms in a collection of <i>Aspergillus lentulus</i> clinical isolates from the United States.","authors":"Adela Martin-Vicente, Ashley V Nywening, Jinhong Xie, Harrison I Thorn, Xabier Guruceaga, Jarrod R Fortwendel","doi":"10.1128/aac.00690-25","DOIUrl":"https://doi.org/10.1128/aac.00690-25","url":null,"abstract":"<p><p><i>Aspergillus fumigatus</i> continues to be the leading cause of invasive aspergillosis. However, the number of cases by drug-resistant cryptic species has increased in recent years. <i>Aspergillus lentulus</i> is a sibling species of <i>Aspergillus</i> section <i>Fumigati</i> that can only be distinguished from <i>A. fumigatus</i> by molecular methods. The clinical importance of this species resides in its low susceptibility to triazoles and intrinsic resistance to amphotericin B, making invasive aspergillosis treatments extremely challenging and producing high mortality rates. In this study, we investigate known molecular mechanisms important for triazole resistance in <i>A. fumigatus</i> in a collection of 25 clinical <i>A. lentulus</i> isolates from the United States. Using CRISPR-Cas9 gene editing technology, we performed <i>cyp51A</i> and <i>hmg1</i> allele replacements between susceptible and resistant isolates. Phenotypic characterization of the resulting mutants, together with mRNA expression analyzes of <i>cyp51A</i>, <i>cyp51B,</i> and the putative ABC efflux pump, <i>abcC</i>, suggests that triazole resistance in our <i>A. lentulus</i> isolates is independent of the mechanisms studied.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0069025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038939","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":"Prevalence of resistance markers of artemisinin, partner drugs, and sulfadoxine-pyrimethamine in Nanyumbu and Masasi Districts, Tanzania between 2020 and 2021.","authors":"Richard O Mwaiswelo, Bruno P Mmbando, Frank Chacky, Fabrizio Molteni, Ally Mohamed, Samwel Lazaro, Bushukatale Samuel, Cristina V Ariani, Sonia Gonçalves, Eleanor Drury, Billy Ngasala","doi":"10.1128/aac.01751-24","DOIUrl":"https://doi.org/10.1128/aac.01751-24","url":null,"abstract":"<p><p>Regular monitoring of the emergence and spread of <i>Plasmodium falciparum</i> markers of resistance against artemisinin, partner drugs, sulfadoxine, and pyrimethamine is important for the treatment and prevention of malaria in Tanzania. Blood samples were collected from febrile and non-febrile children aged 3 to 59 months in Masasi and Nanyumbu Districts between 2020 and 2021. The samples were subjected to molecular analysis for markers of artemisinin, partner drugs, sulfadoxine, and pyrimethamine resistance, including <i>Plasmodium falciparum</i> kelch (<i>Pfk</i>) 13 gene, <i>P. falciparum</i> chloroquine resistance transporter gene (<i>Pfcrt</i>), <i>P. falciparum</i> multidrug resistance gene (<i>Pfmdr</i>) 1, <i>P. falciparum</i> dihydrofolate reductase (<i>Pfdhfr</i>), and <i>P. falciparum</i> dihydropteroate synthase (<i>Pfdhps</i>). A total of 531 blood samples were involved in the analysis. None of the <i>P. falciparum</i> isolates analyzed for <i>Pfk13</i> carried any of the validated markers of artemisinin resistance. <i>Pfcrt</i> CVMNK wild-type haplotype occurred in 88.9% (271/305) of the parasites, and the mutant CVIET haplotype occurred only in 0.7% (2/305). Conversely, the majority of the parasites (24.2% [48/198]) were carrying <i>Pfmdr1</i> NFD haplotype, followed by the wild-type haplotype NYD (19.1% (39/198), and the rest were mixed infections. Quintuple mutation <b><u>IRN</u></b>I-S<b><u>GE</u></b>AA occurred in 54.4% (62/114), and sextuple mutation <b><u>IRN</u></b>I-<b><u>F</u></b>AK<b><u>GS</u></b> occurred only in 0.9% (1/114) of the parasites. No parasite carried any of the validated markers of artemisinin resistance; however, the prevalence of <i>Pfcrt</i> and <i>Pfmdr1</i> resistance markers against the partner drugs reached the saturation point. Sextuple <i>Pfdhfr-Pfdhps</i> mutations occurred only in one patient; therefore, SP remains efficacious for IPTp in the Districts.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0175124"},"PeriodicalIF":4.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039004","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>Burkholderia pseudomallei</i> PenI β-lactamase and variants are potently inhibited by taniborbactam.","authors":"Maria F Mojica, Scott A Becka, Mitchell Edwards, Cullen Myers, Kyoko Uehara, Tsuyoshi Uehara, Tyuji Hoshino, Elise T Zeiser, Cassandra L Chatwin, David A Six, Robert A Bonomo, Krisztina M Papp-Wallace, Michiyoshi Nukaga","doi":"10.1128/aac.00787-25","DOIUrl":"https://doi.org/10.1128/aac.00787-25","url":null,"abstract":"<p><p><i>Burkholderia pseudomallei</i> is a Gram-negative pathogen that causes melioidosis, a severe and often fatal disease. Due to its recognized potential as a bioterrorism agent, it is critical that appropriate antimicrobial agents are available for post-exposure prophylaxis and treatment of melioidosis. Cefepime-taniborbactam is a novel β-lactam-β-lactamase inhibitor combination in clinical development, with promising activity against Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. Herein, we demonstrate the inhibitory activity of taniborbactam against PenI, the class A β-lactamase produced by <i>B. pseudomallei</i>. Isogenic <i>Escherichia coli</i> strains producing PenI and its ceftazidime-resistance-conferring variants (C69Y and P167S) showed ceftazidime minimum inhibitory concentration (MIC) of 64 mg/L for the strain producing PenI and 1,024 mg/L for the strains producing the variants, whereas cefepime MIC was 128-256 mg/L for these three strains. While the addition of avibactam decreased ceftazidime MIC to 1 mg/L for PenI and 8-16 mg/L for the variants, the addition of taniborbactam decreased cefepime MIC to ≤0.5 mg/L for PenI and the variants. Similarly, an 8-fold reduction of the cefepime MIC upon addition of taniborbactam was observed in an avirulent <i>B. pseudomallei</i> strain. Furthermore, taniborbactam inhibited PenI and its C69Y variant with an apparent <i>K</i>_i of 0.11 and 3.1 µM, respectively. Lastly, co-crystallography and molecular dynamics simulations showed that taniborbactam induced the formation of a disulfide bond between Cys77 and Cys123, which destabilizes the deacylation water and strengthens the taniborbactam-PenI complex. These results support the development of cefepime-taniborbactam as a promising agent for the treatment of infections by <i>B. pseudomallei</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0078725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038968","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":"Incorporation of macrophage immune stresses into an intracellular assay of drug tolerance in <i>Mycobacterium tuberculosis</i>.","authors":"Greana Kirubakar, Luana Johnston, Bom Nae Rin Lee, David G Russell, Nelson V Simwela","doi":"10.1128/aac.00795-25","DOIUrl":"https://doi.org/10.1128/aac.00795-25","url":null,"abstract":"<p><p>Development of new and improved tuberculosis (TB) chemotherapies is hampered by antibiotic resistance and drug tolerance by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Phenotypic drug tolerance, a phenomenon where <i>Mtb</i> populations can temporarily survive therapeutic antibiotic concentrations, represents a significant hurdle to TB treatment and is indeed one of the factors responsible for prolonged TB therapy. Assays that can identify compounds with improved efficacy against drug-tolerant <i>Mtb</i> are urgently required to improve TB treatment regimens. Here, we report the development of a 96-well plate assay capable of identifying anti-<i>Mtb</i> drugs with activity against drug-tolerant <i>Mtb</i> in physiologically relevant intracellular environments within macrophages. Primary murine macrophages, modified either by immunological activation or specific CRISPR/Cas9 gene knockouts to generate tolerance-inducing environments, were infected with an <i>Mtb</i> strain constitutively expressing luciferase. Following drug exposure, differences in bacterial survival were measured by bacterial outgrowth after lysis of the host macrophages. By monitoring <i>Mtb</i> luciferase in infected macrophages before, during, and after drug treatment, we confirmed earlier observations that host immune stresses trigger induction of drug tolerance. However, while host stresses induced tolerance against some anti-TB compounds, the same host stresses were synergistic with other anti-TB drugs. Our assay provides the ability to profile the activities of anti-TB drugs on bacteria in intracellular host environments, which is critical to the rational design of drug combinations that provide optimal coverage of the <i>Mtb</i> sub-populations in the infected host.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0079525"},"PeriodicalIF":4.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039016","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":"Therapeutic approach to difficult-to-treat multidrug-resistant enterococcal infections.","authors":"Adrianna M Turner, Paul Kinsella, William R Miller, Glen P Carter, Truc T Tran, Benjamin P Howden, Cesar A Arias","doi":"10.1128/aac.01060-24","DOIUrl":"https://doi.org/10.1128/aac.01060-24","url":null,"abstract":"<p><p>Difficult-to-treat (DTR) enterococcal infections, particularly those caused by multidrug-resistant <i>Enterococcus faecium</i> and <i>Enterococcus faecalis</i>, pose significant clinical challenges due to limited treatment options and high rates of treatment failure, compounded by a paucity of new antimicrobial agents in the development pipeline. Despite advances in understanding resistance mechanisms and <i>in vitro</i> synergistic antibiotic combinations, robust clinical data to guide therapy for severe or DTR enterococcal infections remain limited. This review synthesizes available evidence to inform optimal management strategies, including drug selection and dosing, while highlighting areas needing further research. Given the ongoing threat posed by multidrug-resistant enterococci, we emphasize the importance of gathering robust clinical data to guide best practices for managing these difficult-to-treat infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0106024"},"PeriodicalIF":4.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039119","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":"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":"https://doi.org/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":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and <i>in vitro</i> activity of gepotidacin against bacterial uropathogens, including drug-resistant phenotypes, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3).","authors":"Nicole E Scangarella-Oman, Deborah L Butler, John Breton, Derrek Brown, Cara Kasapidis, Helen Millns, Chun Huang, Caroline R Perry, Amanda J Sheets, Jeremy Dennison, Salim Janmohamed","doi":"10.1128/aac.01640-24","DOIUrl":"https://doi.org/10.1128/aac.01640-24","url":null,"abstract":"<p><p>Two recent Phase 3 trials demonstrated the efficacy of gepotidacin compared with nitrofurantoin to treat uncomplicated urinary tract infections (uUTIs) in females. Pretreatment urine specimens were obtained from all participants. Based on pooled trial data (treatment groups combined), central laboratory culture results identified 1,421 (45%) participants with ≥1 baseline qualifying (≥10⁵ CFU/mL) uropathogen (i.e., pooled microbiological Intent-to-Treat population). <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, and <i>Proteus mirabilis</i> were the most common qualifying uropathogens. Among 1,159 <i>E. coli</i> isolates, 28%, 28%, 15%, and 28% were fluoroquinolone resistant (FQ-R), trimethoprim-sulfamethoxazole resistant (SXT-R), extended-spectrum β-lactamase positive (ESBL+), and multidrug resistant (MDR), respectively. For 114 <i>K</i>. <i>pneumoniae</i> isolates, 25%, 23%, 16%, and 16% were nitrofurantoin resistant, SXT-R, FQ-R, and ESBL+, respectively. Of 67 <i>P</i>. <i>mirabilis</i> isolates, 25%, 21%, and 31% were SXT-R, FQ-R, and MDR, respectively. Gepotidacin MIC₉₀ values against all qualifying uropathogens and drug-resistant phenotypes ranged from 0.25 to 32 µg/mL, with no isolates of Enterobacterales, <i>Staphylococcus saprophyticus</i>, or <i>Enterococcus faecalis</i> considered resistant to gepotidacin. For all uropathogen drug-resistant phenotypes, gepotidacin MIC₉₀ values were similar (i.e., lower, equal to, or 1-dilution higher) compared with the MIC₉₀ of the overall species. Gepotidacin's efficacy, based on therapeutic, clinical, and microbiological success rates, was generally consistent across phenotypic subgroups of <i>E. coli</i>, <i>K. pneumoniae</i>, and <i>P. mirabilis</i>. This pooled analysis represents a robust, contemporary, clinically relevant, and unbiased (i.e., baseline urine specimens obtained from all enrolled participants regardless of uUTI history) collection of data from community-acquired uUTIs in females.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04020341 and NCT04187144.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0164024"},"PeriodicalIF":4.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022800","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":"Efficacy and <i>in vitro</i> activity of gepotidacin against bacterial uropathogens, including subsets with molecularly characterized resistance mechanisms and genotypes/epidemiological clones, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3).","authors":"Nicole E Scangarella-Oman, Deborah L Butler, John Breton, Derrek Brown, Cara Kasapidis, Amanda J Sheets","doi":"10.1128/aac.01639-24","DOIUrl":"https://doi.org/10.1128/aac.01639-24","url":null,"abstract":"<p><p>Gepotidacin, a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial, was noninferior to nitrofurantoin in two pivotal trials (EAGLE-2 and EAGLE-3) in females with uncomplicated urinary tract infections (uUTIs). Using pooled data, gepotidacin <i>in vitro</i> activity and clinical efficacy were evaluated for subsets of molecularly characterized isolates in the microbiological Intent-to-Treat population. The subsets of isolates were characterized based on phenotypic/MIC criteria; all microbiological failure isolates were also characterized. Of 1,159 <i>Escherichia coli</i> isolates<i>,</i> 30% harbored quinolone resistance-determining region (QRDR) mutations; most prevalent was <i>gyrA</i> S83L, D87N (27%). Extended-spectrum β-lactamases (ESBLs) were detected in 13% of <i>E. coli</i> isolates. For 114 <i>Klebsiella pneumoniae</i> isolates, 22% were plasmid-mediated quinolone resistance (PMQR) gene-positive, 11% had QRDR mutations, and 12% had ESBLs. Among 67 <i>Proteus mirabilis</i> isolates, 21% harbored QRDR mutations. Gepotidacin MIC₉₀ values ranged from 1 to 32 µg/mL against qualifying Enterobacterales uropathogens and genotypic subcategories, with no isolates considered resistant to gepotidacin. For all genotypic subcategories, gepotidacin MIC₉₀ values were similar (i.e., lower, equal to, or 1-dilution higher) compared with the overall species (4 µg/mL), with the exception of <i>E. coli</i> isolates with the PMQR <i>qnrS1</i> gene (16 µg/mL); all were gepotidacin-susceptible. For the majority of uropathogens, including those with genotypes likely to cause resistance to standard uUTI therapies, success rates for gepotidacin were similar across genotypic subcategories for each species. These data show gepotidacin's efficacy and <i>in vitro</i> activity against a wide range of uropathogen genotypes. Additionally, these pooled results provide a robust, contemporary data set and insight into current genotypic mechanisms of resistance.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04020341 and NCT04187144.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0163924"},"PeriodicalIF":4.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022810","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}