Antimicrobial Agents and Chemotherapy最新文献

{"title":"Contribution of front-line, standard-of-care drugs to bactericidal responses, resistance emergence, and cure in murine models of easy- or hard-to-treat tuberculosis disease.","authors":"Nathan Peroutka-Bigus, Elizabeth J Brooks, Michelle E Ramey, Hope D'Erasmo, Jackie P Ernest, Allison A Bauman, Lisa K Woolhiser, Radojka M Savic, Anne J Lenaerts, Bree B Aldridge, Jansy P Sarathy, Gregory T Robertson","doi":"10.1128/aac.01901-24","DOIUrl":"10.1128/aac.01901-24","url":null,"abstract":"<p><p>By assessing the standard-of-care regimen for tuberculosis (TB) in BALB/c and C3HeB/FeJ mice, we demonstrate that rifampin, with or without pyrazinamide, is essential for an effective bactericidal response and suppression of resistance. Potency measurements in an <i>in vitro</i> lipid-rich model and a rabbit caseum assay recapitulate the significance of rifampin as a sterilizing agent. These outcomes align with clinical performance, thus emphasizing the value of <i>in vitro</i> predictive tools and murine TB models with human-like pathology.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0190124"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708252","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":"Vesicle inhibition reduces <i>Candida</i> biofilm resistance.","authors":"Min-Ju Kim, Robert Zarnowski, Ryley Jones, Jeniel E Nett, David Andes","doi":"10.1128/aac.00045-25","DOIUrl":"10.1128/aac.00045-25","url":null,"abstract":"<p><p><i>Candida</i> biofilm matrix components are delivered to the extracellular space by vesicles where they deposit and confer biofilm-associated drug resistance. Here, we present evidence that drugs designed to inhibit mammalian exosome production exhibit similar effects on <i>C. albicans</i> extracellular vesicles<i>,</i> ultimately eliminating biofilm matrix assembly. We find that vesicle reduction renders biofilm communities susceptible to the antifungal fluconazole. Our findings argue that vesicle trafficking pathways represent a promising target to optimize for recalcitrant fungal biofilms.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0004525"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708260","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":"D-alanylation of lipoteichoic acids inhibitor provides anti-virulence and anti-resistance effects against methicillin-resistant <i>Staphylococcus epidermidis</i>.","authors":"Alexandre Mahé, Nicolas Verneuil, Delphine Coupri, Axel Hartke, Vincent Cattoir, Isabelle Rincé, Sabrina Gueulle, Xiao Feng, Thierry Lequeux, Emmanuel Pfund, Aurélie Budin-Verneuil","doi":"10.1128/aac.01822-24","DOIUrl":"10.1128/aac.01822-24","url":null,"abstract":"<p><p>Methicillin-resistant <i>Staphylococcus epidermidis</i> (MRSE) is an emerging multidrug-resistant pathogen responsible for numerous healthcare-associated infections. Most of them are resistant to all classes of antibiotics and thus lead to therapeutic impasse. For this reason, identifying new targets and characterizing new drugs are essential. We recently showed that methicillin-resistant <i>Staphylococcus aureus</i> strains deficient in D-alanylation of teichoic acids (TAs) lost resistance to various β-lactams. Here we explore if D-alanylation of TAs might be a druggable target to overcome β-lactam resistance of MRSE using a competitive DltA inhibitor. The binding affinity of a DltA inhibitor with the purified DltA protein was monitored by determining the half maximal inhibitory concentration (IC₅₀). The efficiency of D-alanylation inhibition was determined by quantifying the ester-linked D-alanine content of purified TAs. Minimal inhibition concentrations (MICs) and bactericidal effects of several β-lactams were monitored in the absence or presence of the inhibitor against a panel of clinical MRSE isolates. Finally, the ability of inhibition of D-alanylation (i) to rescue MRSE-infected larvae of <i>Galleria mellonella</i> and (ii) to prevent or eradicate <i>S. epidermidis</i> biofilms was evaluated. The DltA inhibitor showed IC₅₀ in the low µM range, drastically reduced the D-alanine esters content of TAs and re-sensitized MRSE to β-lactams. The most effective treatment was the DltA inhibitor/imipenem combination. Finally, inhibition of D-alanylation significantly reduced the virulence of MRSE in the <i>G. mellonella</i> infection model and strongly reduced the ability of <i>S. epidermidis</i> to form biofilms. All together, our results show the promising nature of the D-alanylation of TAs as a therapeutic target to fight against MRSE infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0182224"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673229","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":"Genomics for antimicrobial resistance-progress and future directions.","authors":"Norelle L Sherry, Jean Y H Lee, Stefano G Giulieri, Christopher H Connor, Kristy Horan, Jake A Lacey, Courtney R Lane, Glen P Carter, Torsten Seemann, Adrian Egli, Timothy P Stinear, Benjamin P Howden","doi":"10.1128/aac.01082-24","DOIUrl":"https://doi.org/10.1128/aac.01082-24","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) is a critical global public health threat, with bacterial pathogens of primary concern. Pathogen genomics has revolutionized the study of bacterial pathogens and provided deep insights into the mechanisms and dissemination of AMR, with the precision of whole-genome sequencing informing better control strategies. However, generating actionable data from genomic surveillance and diagnostic efforts requires integration at the public health and clinical interface that goes beyond academic efforts to identify resistance mechanisms, undertake <i>post hoc</i> analyses of outbreaks, and share data after research publications. In addition to timely genomics data, consideration also needs to be given to epidemiological sampling frames, analysis, and reporting mechanisms that meet International Organization for Standardization (ISO) standards and generation of reports that are interpretable and actionable for public health and clinical \"end-users.\" Importantly, ensuring all countries have equitable access to data and technology is critical, through timely data sharing following the FAIR principles (findable, accessible, interoperable, and re-usable). In this review, we describe (i) advances in genomic approaches for AMR research and surveillance to understand emergence, evolution, and transmission of AMR and the key requirements to enable this work and (ii) discuss emerging and future applications of genomics at the clinical and public health interface, including barriers to implementation. Harnessing advances in genomics-enhanced AMR research and embedding robust and reproducible workflows within clinical and public health practice promises to maximize the impact of pathogen genomics for AMR globally in the coming decade.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0108224"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966831","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":"Impact of hepatic impairment and renal failure on the pharmacokinetics of linezolid and its metabolites: contribution of hepatic metabolism and renal excretion.","authors":"Jinyao Liu, Yingying Pang, Wenyan Li, Juanjuan Sun, Yujie He, Yonghong Guo, Jing Dong","doi":"10.1128/aac.01892-24","DOIUrl":"https://doi.org/10.1128/aac.01892-24","url":null,"abstract":"<p><p>Linezolid, an oxazolidinone antibiotic, is used in patients with liver or kidney disease. However, the effects and mechanisms of hepatic impairment or renal failure on the pharmacokinetics of linezolid and its metabolites (PNU-142586 and PNU-142300) remain unclear. We used carbon tetrachloride-induced impaired hepatic function and 5/6 nephrectomy-induced renal failure rat models to investigate linezolid and metabolite pharmacokinetics. Isolated primary rat hepatocytes were used to evaluate the impact of hepatic impairment or renal failure on linezolid metabolism. Uptake and efflux transport studies were also conducted. The influence of hepatic impairment or renal failure on the pharmacokinetics of linezolid and two metabolites did not differ between intragastric gavage and intravenous administration in rats. Linezolid did not accumulate in the brain, heart, lung, liver, kidney, and small intestinal tissues of the hepatic impairment or renal failure rats. And PNU-142300 did not accumulate in the liver or kidney tissue. Compared to the isolated normal rat hepatocytes, the <i>in vitro</i> hepatic clearance of linezolid in hepatic impairment and renal failure rat hepatocytes decreased by 61.3% and 44.1%, respectively. Organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, Na+-taurocholate co-transporting polypeptide (NTCP), organic anion transporter (OAT)1, OAT3, multidrug resistance-associated protein 2 (MRP2), or multidrug resistance protein 1 (MDR) did not mediate linezolid transport. Hepatic impairment primarily increases linezolid exposure through reduced hepatic metabolism, whereas renal failure increases both linezolid and two metabolites exposure through reduced hepatic metabolism and renal glomerular filtration. These findings guide adjusting the dose of linezolid in patients with hepatic and renal insufficiency.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0189224"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967573","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":"Combating yellow fever virus with 7-deaza-7-fluoro-2'-C-methyladenosine.","authors":"Julia C LeCher, Vivian Vasconcelos Costa, Lauren N Rust, Leda C Bassit, Dharmeshkumar Patel, Sahar Rezaei, Justin Moua, Felipe Rocha da Silva Santos, Matheus Rodrigues Goncalves, Celso Martins Queroz-Junior, Fernanda Martins Marim, Longhu Zhou, Sujin Lee, Tamara McBrayer, Ramyani De, Niloufar Azadi, Mohammad Salman, Keivan Zandi, Franck Amblard, Benjamin Burwitz, Mauro M Teixeira, Raymond F Schinazi","doi":"10.1128/aac.01889-24","DOIUrl":"https://doi.org/10.1128/aac.01889-24","url":null,"abstract":"<p><p>Yellow fever virus (YFV) is a deadly zoonotic flavivirus endemic in tropical/sub-tropical Africa and South America transmitted by mosquito vector (<i>Aedes aegypti</i>; <i>Haemagogus leucocelaenus</i>) to humans and non-human primates. There are no approved antiviral agents for YFV. We previously identified 7-deaza-7-fluoro-2'-C-methyladenosine (DFA) with anti-YFV activity. Interestingly, DFA exhibits pan-activity in vitro against flaviviruses, such as dengue, Japanese encephalitis, Zika, and hepatitis C. This study aimed to expand DFA's anti-flavivirus profile. DFA exhibited potent sub-micromolar anti-YFV activity <i>in vitro</i> against both the vaccine strain (YFV-17D) and a viscerotropic clinical YFV isolate (DakH1279) concomitantly with low cellular cytotoxicity and no notable mitochondrial toxicity. <i>In vivo</i>, efficacy was assessed against both YFV-17DD and a human clinical isolate in A129 and AG129 mouse flavivirus infection models, respectively. DFA significantly reduced virus replication in the livers of YFV-infected mice and the hallmarks of YFV-induced liver damage, including alanine transaminase levels and indocyanine green clearance. Collectively, this work identifies DFA as a potent YFV inhibitor and lays the groundwork for further therapeutic development as a YFV and, potentially, pan-flavivirus therapeutic.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0188924"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952593","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":"The newly identified <i>grdA</i> gene confers high-level plazomicin resistance in <i>Salmonella enterica</i> serovars.","authors":"Ahmed F Hikal, Shaohua Zhao, Steven Foley, Ashraf A Khan","doi":"10.1128/aac.01606-24","DOIUrl":"10.1128/aac.01606-24","url":null,"abstract":"<p><p>Plazomicin, a next-generation aminoglycoside, was recently approved by the U.S. Food and Drug Administration for the treatment of multidrug-resistant complicated urinary tract infections. It is highly effective against most aminoglycoside-modifying enzymes (AMEs). Here, we report that <i>Salmonella enterica</i> strains containing the newly identified gentamicin resistance gene (<i>grdA</i>) are highly resistant to plazomicin. Heterologous expression of <i>grdA</i> in <i>Escherichia coli</i> Δ<i>tolC</i> resulted in plazomicin resistance with minimum inhibitory concentration (MIC) > 256 µg/mL. These findings reveal that GrdA confers significantly higher resistance to plazomicin than the previously known plazomicin-resistant AMEs AA (2)-Ia and APH (2″)-Iva.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0160624"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770921","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":"Inhibitory effect of copper chelators on the budding in <i>Candida albicans</i>.","authors":"Yushi Futamura, Kai Yamamoto, Rachael Uson-Lopez, Harumi Aono, Takeshi Shimizu, Yasuhiro Hori, Kuniki Kino, Hiroyuki Osada","doi":"10.1128/aac.00033-25","DOIUrl":"10.1128/aac.00033-25","url":null,"abstract":"<p><p><i>Candida albicans</i> exhibits a unique dimorphic behavior, allowing it to switch between unicellular budding yeast and filamentous hyphal growth. This dimorphism is crucial for its pathogenicity, influencing processes such as adhesion, invasion, immune evasion, and host response. A comprehensive understanding of the molecular mechanisms governing yeast and hyphal growth, as well as the switch between these forms, is crucial for the development of effective anticandidal therapies. In this study, we screened for small molecules that interfere with the dimorphism of <i>C. albicans</i> and identified the actinomycete metabolite RK-276A/SF2768 as a potent inhibitor of this process. Time-lapse microscopy revealed that SF2768 inhibited hyphal branching and lateral yeast budding during the hyphal-to-yeast transition. Interestingly, SF2768 also suppressed farnesol-induced yeast growth by inhibiting yeast bud formation. The effects of SF2768 were canceled with copper addition, and other copper chelators, such as trientine and d-penicillamine, induced similar phenotypes, indicating that the copper-chelating activity of SF2768 is crucial for its antifungal properties. Furthermore, copper ions induced both hyphal and yeast bud formation. These findings strongly suggest that copper ions play a role in <i>Candida</i> budding, and the copper chelators could be developed as novel antifungal agents against not only dimorphic <i>Candida</i> spp. but also non-dimorphic <i>Candida</i> spp.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0003325"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810331","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":"Distribution of ganciclovir in the porcine central nervous system.","authors":"Johan Mikkel Guldbæk, Theis Mariager, Mikkel Dreyer Nielsen, Jacob Holmen Terkelsen, Roland Nau, Carsten Reidies Bjarkam, Henrik Nielsen, Jacob Bodilsen","doi":"10.1128/aac.01815-24","DOIUrl":"10.1128/aac.01815-24","url":null,"abstract":"<p><p>Ganciclovir is often used compassionately for encephalitis due to cytomegalovirus (CMV) and human herpes virus 6b (HHV-6b). Ganciclovir pharmacokinetic studies in the central nervous system (CNS) generally rely on single measurements in the cerebrospinal fluid (CSF) or homogenized brain tissue. Therefore the objective was to compare brain extracellular fluid (ECF) concentrations of ganciclovir with plasma and CSF concentrations in a porcine model, using microdialysis during a 24 h period. Six Danish landrace pigs (female, age 4 months, 31-37 kg) received two weight-adjusted intravenous doses of ganciclovir. Unbound ganciclovir concentrations were determined by microdialysis over 24 h in five compartments: CSF (lateral ventricle, cisterna magna, and lumbar) and brain ECF (cortical and subcortical). Data were compared with paired plasma samples. Ganciclovir concentrations >IC₅₀ for CMV (1.6 µg/mL) were achieved in all compartments. Concentrations >IC₉₀ for CMV (8.3 µg/mL) were only achieved in plasma and the lumbar CSF compartment. The concentration time curves indicated higher lumbar and cisternal CSF concentrations than ECF concentrations. The ECF compartments achieved greater maximum concentration (C_max), area under the concentration time curve (AUC), and time >IC₅₀ after the second dose, and an accumulation ratio (R_ac) >1. The greater C_max, AUC, time >IC₅₀, and R_ac >1 in the ECF compartments with repeated dosages suggest that therapeutic concentrations may be achieved during long-term treatment. A higher loading dose might be warranted to improve early viral inhibition.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0181524"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673233","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":"Antibiotic killing of drug-induced bacteriostatic cells.","authors":"Teresa Gil-Gil, Brandon A Berryhill","doi":"10.1128/aac.00156-25","DOIUrl":"10.1128/aac.00156-25","url":null,"abstract":"<p><p>There is a long-standing belief that bacteriostatic drugs are inherently antagonistic to the action of bactericidal antibiotics. This belief is primarily because the action of most bactericidal antibiotics requires the target bacteria to be growing. Since bacteriostatic drugs stop the growth of treated bacteria, these drugs would necessarily work against one another. Our results question this long-standing belief by demonstrating conditions where sequential treatment with a bacteriostatic then bactericidal antibiotic is as or more effective than treatment with a bactericidal drug alone. These results raise the need to investigate the pharmacodynamics of the joint action of bacteriostatic and bactericidal antibiotics <i>in vitro</i> and <i>in vivo</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0015625"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708249","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}