International Journal of Antimicrobial Agents最新文献

{"title":"Rethinking dormancy: Antibiotic persisters are metabolically active, non-growing cells.","authors":"K M Taufiqur Rahman, Ruqayyah Amaratunga, Xuan Yi Butzin, Abhyudai Singh, Tahmina Hossain, Nicholas C Butzin","doi":"10.1016/j.ijantimicag.2024.107386","DOIUrl":"10.1016/j.ijantimicag.2024.107386","url":null,"abstract":"<p><strong>Objectives: </strong>Bacterial persisters are a subpopulation of multidrug-tolerant cells capable of surviving and resuming activity after exposure to bactericidal antibiotic concentrations, contributing to relapsing infections and the development of antibiotic resistance. In this study, we challenge the conventional view that persisters are metabolically dormant by providing compelling evidence that an isogenic population of Escherichia coli remains metabolically active in persistence.</p><p><strong>Methods: </strong>Using transcriptomic analysis, we examined E. coli persisters at multiple time points following exposure to bactericidal concentrations of ampicillin (Amp). Some genes were consistently upregulated in Amp treated persisters compared to the untreated controls, a change that can only occur in metabolically active cells capable of increasing RNA levels.</p><p><strong>Results: </strong>Some of the identified genes have been previously linked to persister cells, while others have not been associated with them before. If persister cells were metabolically dormant, gene expression changes over time would be minimal during Amp treatment. However, network analysis revealed major shifts in gene network activity at various time points of antibiotic exposure.</p><p><strong>Conclusions: </strong>These findings reveal that persisters are metabolically active, non-dividing cells, thereby challenging the traditional view that they are dormant.</p>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":" ","pages":"107386"},"PeriodicalIF":4.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647972","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":"Model-Informed Drug Development (MIDD) for Antimicrobials","authors":"Yu-Wei Lin ,&nbsp;S.Y. Amy Cheung","doi":"10.1016/j.ijantimicag.2024.107392","DOIUrl":"10.1016/j.ijantimicag.2024.107392","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107392"},"PeriodicalIF":4.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643724","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":"Effect of clinically relevant antibiotics on bacterial extracellular vesicle release from Escherichia coli.","authors":"Panteha Torabian, Navraj Singh, James Crawford, Gabriela Gonzalez, Nicholas Burgado, Martina Videva, Aidan Miller, Janai Perdue, Milena Dinu, Anthony Pietropaoli, Thomas Gaborski, Lea Vacca Michel","doi":"10.1016/j.ijantimicag.2024.107384","DOIUrl":"10.1016/j.ijantimicag.2024.107384","url":null,"abstract":"<p><p>Sepsis, a leading cause of death in hospitals, can be defined as a dysregulated host inflammatory response to infection, which can lead to tissue damage, organ failure and cardiovascular complications. Although there is no cure for sepsis, the condition is typically managed with broad-spectrum antibiotics to eliminate any potential bacterial source of infection. However, a potential side effect of antibiotic treatment is the enhanced release of bacterial extracellular vesicles (BEVs), membrane-bound nanoparticles containing proteins and other biological molecules from their parent bacterium. Some of the Gram-negative extracellular vesicle (EV) cargo, including peptidoglycan associated lipoprotein and outer membrane protein A, have been shown to induce both acute and chronic inflammation in host tissue. It was hypothesized that the antibiotic concentration and mechanism of action may affect the amount of released BEVs, which could potentially exacerbate the host inflammatory response. This study evaluated nine clinically relevant antibiotics for their effect on EV release from Escherichia coli. Several beta-lactam antibiotics caused significantly more EV release, while quinolone and aminoglycoside antibiotics caused less vesiculation. Further study is warranted to corroborate the correlation between an antibiotic's mechanism of action and its effect on EV release, but these results underline the importance of antibiotic choice when treating patients with sepsis.</p>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":" ","pages":"107384"},"PeriodicalIF":4.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619427","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":"NpmC - a novel A1408 16S rRNA methyltransferase in the gut of humans and animals.","authors":"Bosco R Matamoros, Carlos Serna, Emilia Wedel, Natalia Montero, Finn Kirpekar, Bruno Gonzalez-Zorn","doi":"10.1016/j.ijantimicag.2024.107382","DOIUrl":"10.1016/j.ijantimicag.2024.107382","url":null,"abstract":"<p><p>NpmA and NpmB are 16S rRNA methyltransferases that act on residue A1408 and confer high-level resistance to almost all aminoglycosides; however, these methyltransferases are rarely reported. A novel gene, npmC, was identified after analysisng all world-wide available metagenomic projects in a One Health context. This gene has a high level of similarity (91.5%) with npmA and up to 92.7% similarity at amino acidic level. The protein encoded by this gene presents the conserved motifs required for A1408 methylation. npmC was synthesized and its expression in Escherichia coli resulted in a high level of resistance to 4,5-disubstituted 2-deoxystreptamine (2-DOS) and 4-monosubstituted 2-DOS aminoglycosides, as well as moderate resistance to 4,6-disusbstituted 2-DOS aminoglycosides, including the last resort aminoglycoside, plazomicin. Methylation at residue A1408 was confirmed by mass spectrometry assays. Analysis of the npmC gene background revealed that its genetic context was associated with different insertion sequences that could mobilise the gene. Similarities in the genetic context between npmC and npmA indicate that they share a common ancestor. The immediate genetic context of this methyltransferase indicates a high relationship to the Eubacteriales order. This finding reveals the dark matter of the microbiome as a potential source of novel resistance genes, expands the list of the true pan-aminoglycoside 16S rRNA methyltransferases, which threaten the usefulness and development of next-generation aminoglycosides.</p>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":" ","pages":"107382"},"PeriodicalIF":4.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619975","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":"Safety, Tolerability, and Pharmacokinetics of a Novel Anti-Influenza Agent ZX-7101A Tablets in Healthy Chinese Participants: A First-in-Human Phase I Clinical Study.","authors":"Junzhen Wu, Qiong Wei, Yi Jin, Guoying Cao, Jicheng Yu, Xiaojie Wu, Xinyi Yang, Yilin Li, Mei Liu, Xiaoli Qin, Jingwen Ai, Yin Wang, Wenhong Zhang, Jing Zhang","doi":"10.1016/j.ijantimicag.2024.107381","DOIUrl":"10.1016/j.ijantimicag.2024.107381","url":null,"abstract":"<p><strong>Background: </strong>We investigated the safety, tolerability, and pharmacokinetics of ZX-7101A tablets, a novel cap-dependent endonuclease inhibitor, in healthy participants in a first-in-human study.</p><p><strong>Methods: </strong>The single ascending dose (SAD) part of the study included 40, 80, 160, 240, and 320 mg dose cohorts with10 participants in each dose cohort (8 participants received ZX-7101A tablets and 2 participants received placebo). The food effect (FE) part of the study was a randomised, 2-cycle, 2-way crossover design, which enrolled 16 participants to receive a single oral dose of 80 mg ZX-7101A tablets.</p><p><strong>Results: </strong>ZX-7101A tablets were safe and well-tolerated in both SAD and FE studies. No participant died or experienced SAE, or withdrew prematurely. The prodrug ZX-7101A was rapidly transformed into the active ingredient ZX-7101 after a single oral dose of 40-320 mg. The blood concentration of ZX-7101A was below the lower limit of quantification at most time points. ZX-7101 reached peak concentration about 3-4 h postdose in all dose cohorts. The elimination half-life of ZX-7101 was 83.01-125.55 h, and AUC_0-24 was 1655.4-11483.7 h*ng/mL. The FE part showed that the high-fat meal significantly affected the exposure parameters compared to the fasted condition. The C_max and AUC_0-t of ZX-7101 under the fasted condition were 1.73 and 1.78 times those under the fed condition, respectively.</p><p><strong>Conclusions: </strong>A single oral dose of 40 mg and 80 mg ZX-7101A tablets achieved sufficient ZX-7101 exposure for effectively inhibiting influenza A and B viruses and avian influenza viruses. These findings support 40 mg and 80 mg of ZX-7101A tablets as single dose regimens for use in phase II/III clinical trials. This study was registered at chinadrugtrials.org.cn (identifier: CTR20212778).</p>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":" ","pages":"107381"},"PeriodicalIF":4.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619424","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 has immunoregulative effects in LPS-induced vitro experimental model via inhibiting inflammation and ferroptosis","authors":"Mohan Ju ,&nbsp;Min Hao ,&nbsp;Dongfang Lin,&nbsp;Shuang Liu","doi":"10.1016/j.ijantimicag.2024.107374","DOIUrl":"10.1016/j.ijantimicag.2024.107374","url":null,"abstract":"<div><h3>Background</h3><div>Cefiderocol is a new catecholamine-containing siderophore cephalosporin. It, however, remains unclear how cefiderocol modulates the immune response of the host.</div></div><div><h3>Objectives</h3><div>This study elucidated whether cefiderocol exerts immunoprotective effects in an in vitro experimental model induced with lipopolysaccharide (LPS).</div></div><div><h3>Methods</h3><div>Mouse macrophage RAW 264.7 cells were exposed to LPS (100 ng/mL) or LPS + cefiderocol (40 mg/L) to assess the immunomodulatory effect of cefiderocol in vitro. ELISA was performed on cell culture supernatants to estimate cytokine levels. Ferroptosis level was also quantified by detecting intracellular reactive oxygen species and iron levels through flow cytometry analysis. Malondialdehyde and glutathione (GSH) levels were estimated by ELISA. We conducted western blotting assay for evaluating key ferroptosis pathway proteins.</div></div><div><h3>Results</h3><div>Cefiderocol alleviated LPS-induced inflammation by reducing IL-6, TNF-α, and IL-1β production levels and enhancing the IL-10 production level. Further analysis to determine the underlying mechanism revealed that cefiderocol inhibited ferroptosis; this was confirmed by reduced reactive oxygen species, malondialdehyde, and Fe²⁺ ion levels; increased GSH levels; upregulated expression of solute carrier family 7 member 11, GSH peroxidase 4, nuclear factor erythroid 2-related factor 2, and ferroptosis suppressor protein 1; and downregulated expression of acyl-CoA synthetase long-chain family member 4.</div></div><div><h3>Conclusions</h3><div>Cefiderocol may play a key role in reducing inflammation by decreasing inflammatory cytokine release and suppressing ferroptosis.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107374"},"PeriodicalIF":4.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603820","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":"Title Page & Editorial Board","authors":"","doi":"10.1016/S0924-8579(24)00292-9","DOIUrl":"10.1016/S0924-8579(24)00292-9","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 5","pages":"Article 107376"},"PeriodicalIF":4.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578173","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":"Isoniazid prophylaxis based on tuberculosis risk factors in living kidney transplantation recipients: A retrospective cohort study","authors":"Hao Zhang ,&nbsp;Jun Zeng ,&nbsp;Tingting Zhu ,&nbsp;Tao Lin ,&nbsp;Turun Song","doi":"10.1016/j.ijantimicag.2024.107375","DOIUrl":"10.1016/j.ijantimicag.2024.107375","url":null,"abstract":"<div><h3>Background</h3><div>Tuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection. However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain.</div></div><div><h3>Methods</h3><div>This study included all living-donor kidney transplant recipients between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with INH (R-INH), the risk group without INH (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed.</div></div><div><h3>Results</h3><div>A total of 1348 patients were divided into R-INH (<em>n</em> = 108), R-NINH (<em>n</em> = 371), and NR (<em>n</em> = 869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (hazard ratios, 0.55, 95% confidence interval, 0.07–4.21, <em>P</em> = 0.564), whereas it was significantly higher in R-NINH (hazard ratios, 5.04, 95% confidence interval, 2.64–9.62, <em>P</em> &lt; 0.001). The median time from transplantation to TB was 19 months (interquartile range: 6–39), and 18 patients (38.3%) were diagnosed within 1 year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%).</div></div><div><h3>Conclusions</h3><div>A 6-month INH regimen based on TB risk factors is effective and well-tolerated for preventing post-transplant TB in kidney transplant recipients.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107375"},"PeriodicalIF":4.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564412","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":"Machine learning accelerates the discovery of epitope-based dual-bioactive peptides against skin infections","authors":"Le Fu ,&nbsp;Xu Zheng ,&nbsp;Jiawen Luo ,&nbsp;Yiyu Zhang ,&nbsp;Xue Gao ,&nbsp;Li Jin ,&nbsp;Wenting Liu ,&nbsp;Chaoqun Zhang ,&nbsp;Dongyu Gao ,&nbsp;Bocheng Xu ,&nbsp;Qingru Jiang ,&nbsp;Shuli Chou ,&nbsp;Liang Luo","doi":"10.1016/j.ijantimicag.2024.107371","DOIUrl":"10.1016/j.ijantimicag.2024.107371","url":null,"abstract":"<div><h3>Objectives</h3><div>Skin injuries and infections are an inevitable part of daily human life, particularly with chronic wounds, becoming an increasing socioeconomic burden. In treating skin infections and promoting wound healing, bioactive peptides may hold significant potential, particularly those possessing antimicrobial and anti-inflammatory properties. However, obtaining these peptides solely through traditional wet laboratory experiments is costly and time-consuming, and peptides identified by current computer-assisted predictive models largely lack validation of their effects via wet laboratory experiments. Consequently, this study aimed to integrate computer-assisted methods and traditional wet laboratory experiments to identify anti-inflammatory and antimicrobial peptides.</div></div><div><h3>Methods</h3><div>We developed a computer-assisted mining pipeline to screen potential peptides from the epitopes of the major histocompatibility complex class II.</div></div><div><h3>Results</h3><div>The peptide AIMP1 was identified, with the ability to physically damage <em>Escherichia coli</em> by increasing bacterial cell membrane permeability, and with the ability to inhibit inflammation by binding to endotoxin-lipopolysaccharide. Additionally, in an LPS-induced inflammation animal model, AIMP1 slightly increased levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and in a skin wound infection animal model, AIMP1 effectively accelerated healing, reduced levels of these pro-inflammatory cytokines, and showed no acute hepatotoxicity or nephrotoxicity.</div></div><div><h3>Conclusions</h3><div>In conclusion, this study not only developed a computer-assisted mining pipeline for identifying anti-inflammatory and antimicrobial peptides but also successfully pinpointed the peptide AIMP1, demonstrating its therapeutic potential for skin injury treatment.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107371"},"PeriodicalIF":4.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564414","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":"Hypervirulent Carbapenem-Susceptible Klebsiella pneumoniae ST412/K57 with Strong Biofilm Formation: Association with gas gangrene and sepsis","authors":"Wenhao Wu ,&nbsp;Shuangling Ni ,&nbsp;Yi Zheng ,&nbsp;Piaopiao Zhang ,&nbsp;Yan Jiang ,&nbsp;Xi Li ,&nbsp;Yunsong Yu ,&nbsp;Tingting Qu","doi":"10.1016/j.ijantimicag.2024.107373","DOIUrl":"10.1016/j.ijantimicag.2024.107373","url":null,"abstract":"<div><div>Hypervirulent <em>Klebsiella pneumoniae</em> (hvKp) poses a serious public health threat. Gas gangrene caused by hvKp is rarely reported and potentially results in a poor prognosis. This study describes the case of a hospitalised patient with gas gangrene and sepsis caused by hvKP. Carbapenem-susceptible hypervirulent <em>Klebsiella pneumoniae</em> (CS-hvKp) strains KPLSN and KPLSX were isolated from the knee joint pus and blood specimens of the patient for further investigations. Whole genome sequencing revealed that KPLSN and KPLSX were highly homologous (single nucleotide polymorphisms [SNPs]&lt;10) and belonged to ST412/K57. The minimum inhibitory concentration and minimum bactericidal concentration under biofilm values of meropenem in KPLSN and KPLSX were significantly higher than in the planktonic state (&gt;128 mg/L vs. 0.25 mg/L, <em>P</em>&lt;0.0001). These two strains had high biofilm formation ability, and the results from fluorescence staining experiments showed that they were not easily killed by meropenem in the biofilm state. KPLSN and KPLSX showed high capsule production and were confirmed to have high virulence through experiments with the <em>Galleria mellonella</em> infection model and the BALB/c mice abdominal infection model. The persistent symptoms may be due to enhanced biofilm and capsule formation. Phylogenetic analysis of global ST412 strains showed their evolution towards higher virulence and resistance. These results emphasise the critical need for judicious antibiotic use and novel therapeutic approaches to combat special infections caused by these pathogens.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107373"},"PeriodicalIF":4.9,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564411","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}