Antimicrobial Agents and Chemotherapy最新文献

Sorfequiline (TBAJ-876) is a novel diarylquinoline under development for tuberculosis. In a first-in-human, multiple-ascending-dose study, electrocardiogram and pharmacokinetic data were analyzed to assess cardiac repolarization. Placebo-corrected change-from-baseline in QTcF (ΔΔQTcF) ranged from -11.4 to +2.4 ms without dose dependency. Concentration-QTc modeling showed a shallow, non-significant slope. The predicted mean effect on ΔΔQTcF at the maximum geometric mean C_max of sorfequiline's M3 metabolite was -1.1 ms (90% CI -9.5 to 7.4).CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06058299.

Invasive infections caused by the yeast Candida albicans are a significant health concern due to their high rates of mortality and morbidity. Current treatment guidelines recommend echinocandin drugs as a primary therapeutic option. Despite the prevailing view that these drugs act extracellularly, evidence suggests that the echinocandin caspofungin can enter fungal cells via an as-yet-unidentified mechanism, with the implications of this internalization remaining unknown. Based on our previous findings demonstrating that caspofungin can bind iron and considering its structural resemblance to ferrichrome-type cyclic hexapeptide siderophores, we hypothesize that siderophore transporters could be involved in caspofungin uptake. In C. albicans, at the transcriptional level, caspofungin mimics a high iron response, which correlates with the increase in intracellular iron levels in drug-treated cells. This increase depends on the siderophore transporter Sit1, as a C. albicans mutant lacking Sit1 does not experience such an increase. Heterologous expression of Sit1 made Saccharomyces cerevisiae cells more sensitive to caspofungin, while C. albicans cells lacking Sit1 or a S. cerevisiae mutant of all siderophore transporters were more tolerant to the drug. Experiments using a newly synthesized fluorescent caspofungin molecule and mass spectrometry confirmed that caspofungin accumulation in yeast is partially mediated by Sit1. Overall, this work identifies siderophore transporters as important players in caspofungin uptake and tolerance in yeast.

Carbapenem-resistant gram-negative ventriculitis is a life-threatening infection with limited treatment options. H. Jiang, Y. Hu, J. Cai, J. Zhang, et al. (Antimicrob Agents Chemother 70:e00943-25, 2026, https://doi.org/10.1128/aac.00943-25) describe two patients with this condition who were successfully treated with intraventricular polymyxin B. Their report highlights uneven antibiotic distribution within the ventricles, the influence of cerebrospinal fluid drainage on intraventricular drug concentrations, and cure with intraventricular polymyxin B alone. These findings raise important questions about optimal intraventricular antimicrobial dosing and whether concurrent intravenous therapy is needed in healthcare-associated ventriculitis.

Children with invasive aspergillosis (IA) experience significant morbidity and mortality. Posaconazole is a broad-spectrum triazole antifungal agent indicated for IA treatment in adolescents and adults. A phase 2, open-label, noncomparative, multinational clinical trial in pediatric participants (2-to-<18 years old, body weight ≥10 kg) with possible, probable, or proven IA was conducted. Participants received intravenous posaconazole for ≥1 week, after which they could switch to oral posaconazole for a total treatment duration <12 weeks. Posaconazole dosing and selection of oral formulation (tablet or oral suspension [PFS]) were weight-based. The primary endpoint was safety, assessed as treatment-related adverse events (TRAE) through 14 days after treatment cessation. Global clinical response was a secondary and all-cause mortality an exploratory endpoint. PFS palatability was assessed using a 5-point scale. Thirty-one participants (proven/probable IA n = 9, possible invasive fungal disease n = 22) received ≥1 dose of posaconazole; 14 were 2 to <12 years, and 17 were 12 to <18 years old. Median treatment duration was 49 (range: 2-88) days. Seven participants (22.6%; 95% confidence interval [CI]: 9.6, 41.1) had ≥1 TRAE (grade 1 or 2, all resolved). One participant discontinued treatment due to a nonserious TRAE. Favorable global clinical response rates through weeks 6 and 12 were 67.7% (95% CI: 48.6, 83.3) and 77.4% (95% CI: 58.9, 90.4), respectively (no relapses). Day 114 all-cause mortality was 12.9%. No participants experienced problems taking PFS, and 90.0% rated PFS palatability as very good to neutral. Posaconazole was well tolerated and associated with high clinical response rates in pediatric patients with IA.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04218851.

Schistosomiasis is a neglected tropical disease with limited treatment options and growing concerns over praziquantel resistance. We evaluated a series of 12 synthetic compounds for antiparasitic activity against Schistosoma mansoni adult worms in vitro. Isoindole-1,3-dione derivatives were inactive, whereas four imidazolidine-2,4-dione derivatives displayed selective antischistosomal activity with low cytotoxicity in mammalian cells. These findings highlight imidazolidine-2,4-dione as a promising scaffold for the development of new therapeutic agents against schistosomiasis.

Identifying the genetic relatedness of resistant bacterial pathogens in healthcare settings can help identify undetected transmission events and outbreaks. However, current methods are time- and resource-intensive. We evaluated a rapid neighbor typing method paired with long-read sequencing for assessment of genetic relatedness. Utilizing a data set of primary clinical samples and published isolate data from two outbreaks of Escherichia coli, we applied genomic neighbor typing of long-read sequence data to rapidly estimate genetic relatedness. We assessed the correlation between neighbor typing predicted genetic distance and pairwise genetic distance from short-read draft whole genomes for all sample pairs. Predicted genetic trees using neighbor typing were compared to reference genetic trees generated using mash distances and maximum-likelihood (ML) methods to assess the extent of agreement, along with metrics of cluster similarity (cluster comparability and Baker's gamma index [BGI]) and tree topology similarity (generalized Robinson-Foulds [GRF] metric). For all three data sets, we found strong correlations between the reference methods and predicted genetic distances (Spearman's rho = 0.75-0.95, P < 0.001), which improved when using a lineage score-informed approach (Spearman's rho = 0.93-0.94, P < 0.001). Predicted genetic trees and clusters from neighbor typing were comparable to those generated using either mashtree or an ML method, with a range of cluster comparability of 85.8-99.5%, BGIs of 0.8-0.95, and GRF values of 0.34-0.8. Pairing the neighbor typing method with long-read sequencing can enable accurate predictions of the relatedness of E. coli samples and isolates, and could potentially be used as a rapid outbreak surveillance tool.

RNA interference (RNAi) therapeutics targeting hepatitis B virus (HBV) RNAs and monoclonal antibodies (mAbs) targeting HBV surface antigen (HBsAg) represent potential strategies for enabling functional cure in chronic HBV patients. Tobevibart (VIR-3434) is an investigational, Fc-engineered human mAb that targets HBsAg with pan-genotypic neutralizing activity. Elebsiran (VIR-2218) is an investigational small interfering RNA targeting a conserved region of the HBV genome. The in vitro antiviral activity of elebsiran was assessed in HBV-infected primary human hepatocytes and hepatoma cells and showed potent inhibition of viral markers HBeAg (EC₅₀ of 2.5 nM and 53.7 pM, respectively) and HBsAg (EC₅₀ of 1.4 nM and 66.5 pM, respectively). Tobevibart and elebsiran activity in vivo was determined using two well-established HBV mouse models: AAV-HBV transduced C57BL/6 mice and human liver-chimeric mice. Mice were treated with a monotherapy or a combination of muHBC34 (the murinized parental mAb of tobevibart) and elebsiran at different doses. In both models, the mouse surrogate of tobevibart or elebsiran monotherapy was effective in reducing blood HBsAg levels. Combined treatment improved suppression of HBsAg (maximum mean reductions of 2.81 log in the AAV-HBV model and 2.51 log in human liver-chimeric mice) and HBV DNA over monotherapy. Tobevibart and elebsiran have been tested in clinical trials for the treatment of chronic hepatitis B and chronic hepatitis Delta.

Human norovirus (HNoV) is a major cause of gastroenteritis worldwide, for which no antiviral therapies exist to date. Previously, our lab has demonstrated that both HNoV and murine norovirus (MNV1) are highly dependent on the expression of the Ras-GTPase-activating protein-binding protein 1 (G3BP1), a cellular protein mostly involved in the assembly of stress granules. We, therefore, hypothesize that targeting G3BP1 could be a promising antiviral strategy against noroviruses. Here, we designed a proof-of-concept study to test targeted protein degradation as a mechanism to induce the specific proteolysis of G3BP1 via the proteasome. To do so, we generated a cellular platform for the overexpression of G3BP1 fused to the bacterial protein Halotag (HaloG3BP1). First, we showed that MNV1 replication is restored in G3BP1-knockout (ΔG3BP1) cells complemented with HaloG3BP1. We then used a PROteolysis TArgeting Chimera (PROTAC) directed toward the Halotag (HaloPROTAC) to induce the specific degradation of HaloG3BP1. We further demonstrate that proteolysis of G3BP1 reduces MNV1 replication, leading to a lower infectious virus yield and preventing virus-induced cell death. We also confirmed that the mechanism of HaloPROTAC3 is mediated via the recruitment of Cullin2-VHL E3-ubiquitin ligase. Our findings add to the body of evidence supporting that targeting of the cellular protein G3BP1 can be used as an antiviral approach and validates the use of PROTACs for the efficient and specific degradation of cellular factors as a feasible methodology to combat viral diseases.

Vancomycin remains a key treatment for infections caused by β-lactam-resistant gram-positive cocci. While there is unanimity that only drug not bound to plasma proteins is pharmacologically active, a wide range of values and interdependencies for the unbound fraction (f_u) of vancomycin have been reported in the past. In the present study, we evaluated 706 plasma samples from 228 adult in-patients who were sent for therapeutic drug monitoring. Total and free concentrations of vancomycin were analyzed by a validated method using ultrafiltration and HPLC-UV. Covariate effects on f_u were assessed by a linear mixed-effects model. The mean unbound fraction was 72.2 ± 5.5% (coefficient of variation 7.7%, range 53-93%), the intra-individual and inter-individual variability were low (median coefficient of variation 5.7% and 6.4%, respectively). The unbound fraction was independent of total vancomycin, plasma albumin or total protein concentrations, or other biochemical or demographic variables, and did not differ between patients treated inside or outside of intensive care (P=0.465). Linear mixed-effects modeling confirmed low overall variability (coefficient of variation 7.0%), decomposed into 2.2% inter-individual, 3.8% inter-occasion, and 5.5% residual variability. Method comparison showed an excellent agreement between high-performance liquid chromatography with ultraviolet detection (HPLC-UV) and the immunoassay used for routine drug monitoring (bias +0.2%). Free concentrations of vancomycin can be reliably predicted from total concentrations. An unbound fraction of approximately 70% provides a robust and clinically useful estimate. Remaining variability appears to be primarily methodological, and not of clinical relevance.