Journal of enzyme inhibition and medicinal chemistryShuaibu Abdullahi Hudu, Najlaa Saadi, Emad A Morad, Albashir Tahir, Abdulgafar Olayiwola Jimoh
Candida auris is a major public health concern worldwide due to its efficient transmission, environmental persistence, and broad resistance to approved antifungal classes. This review consolidates recent pharmacological developments in this regard, focusing on mechanistic insights and late-stage therapeutics. Novel agents demonstrate activity against multidrug- and pan-resistant isolates via distinct mechanisms of action and enhanced specific binding to CYP51. Repositioned drugs, host-defense peptides, and quorum-sensing modulators also expand the treatable spectrum, particularly for biofilm-associated and device-related infections. Concurrently, artificial intelligence (AI)-guided discovery, nanocarrier-enabled delivery, and multi-omics profiling are greatly accelerating target identification and enhancing the drug metabolism of small-molecule fragments. The emerging combined approaches mark a transition towards mechanism-based antifungal development to combat the increasing clinical burden posed by C. auris. Ongoing integration of precision diagnostics, pharmacodynamic optimization, and novel discovery platforms will be key to translating these advances into durable, real-world therapeutic solutions.
Journal of enzyme inhibition and medicinal chemistryHung-Pei Tsai, Tzong-Huei Lee, Hong-Liang Lin, Tzu-Wei Lin, Wen-Hsin Chang, Chien-Ju Lin
Trichodermin, a sesquiterpene antibiotic from Trichoderma species, shows anticancer potential. In this study, anti-glioblastoma activity was evaluated by (3-(4,5-di methyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay, colony formation, lactate dehydrogenase (LDH) release assay, flow cytometry, wound-healing, transwell invasion, adhesion, Western blot, combination-index analysis, and an orthotopic luciferase glioblastoma mouse model. Trichodermin reduced viability and clonogenicity and increased LDH release of T98G and A172 cells. Trichodermin induced G2/M arrest with p53 activation and downregulation of cyclin B, cyclin A, and cyclin-dependent kinase 1 (CDK1). In addition, trichodermin induced caspase-dependent apoptosis. Invasion, wound healing, and adhesion were suppressed with modulation of epithelial-mesenchymal transition (EMT)-related proteins. Combination index analysis demonstrated a synergistic interaction between trichodermin and temozolomide, possibly due to increased apoptosis. In the mouse model, intraperitoneal trichodermin inhibited intracranial tumour growth and prolonged survival, and increased cleaved caspase-3 expression in tumour tissues. These findings indicate that trichodermin exerts anti-glioblastoma activity and warrants further preclinical evaluation as a potential adjunct to temozolomide therapy.
Gut microbesBeatriz Nafria, Olga P Nyssen, Jone Narbaiza, Mila Montes, Pablo Parra, Javier P Gisbert, Luis Bujanda
BACKGROUND & AIMS: Antibiotic resistance is a major determinant of the efficacy of Helicobacter pylori (H. pylori) eradication treatment. Our objective was to evaluate the prevalence and geographical distribution of primary antibiotic resistance in patients infected with H. pylori across Europe over the last four decades. METHODS: Bibliographical searches were conducted from 1990 to 2024 in the PubMed database with no language restrictions. Selected studies evaluated the primary resistance of H. pylori to clarithromycin, metronidazole, levofloxacin, amoxicillin, tetracycline and rifampicin in adults. Data were grouped by country and time intervals (1990-1999, 2000-2009, 2010-2019, 2020-2024) to identify potential trends. High resistance thresholds were defined as ≥15% for clarithromycin and levofloxacin, and ≥30% for metronidazole. RESULTS: A total of 216 studies were included: 188 with information on clarithromycin resistant strains (86,917 patients), 138 on metronidazole (83,995 patients), and 77 on levofloxacin (40,619 patients). The overall prevalence of primary resistance to clarithromycin, levofloxacin, and metronidazole was 16% (95% confidence interval, 7-24%), 18% (10-21%), and 33% (29-36%), respectively. Primary resistance to clarithromycin and levofloxacin increased steadily across all periods, reaching 24% and 21%, respectively, in the most recent period. Primary resistance to amoxicillin, tetracycline, and rifampicin remained low, at 2.3%, 1%, and 4%, respectively. Overall, Southern European countries had higher resistance rates than Northern European countries. CONCLUSIONS: In Europe, the prevalence of primary H. pylori resistance to clarithromycin and levofloxacin has increased over time and is high in recent years. Variability exists between countries, with Southern European regions showing higher rates.
PulmonologyMarcela Bhering, Carla Conceição, Martha Oliveira, Ana Paula Razal Dalvi, Marcelo Cordeiro-Santos, Adriana Rezende Moreira, Anna Cristina Calçado Carvalho, Ali…
BACKGROUND: Tuberculosis infection (TBI) diagnosis in BCG-vaccinated, high-burden settings remains challenging. RESEARCH QUESTION: We aimed to assess the sensitivity, specificity, and safety of the C-tuberculin skin test (C-TST), compared with PPD RT-23, for tuberculosis infection in BCG-vaccinated adults. STUDY DESIGN AND METHODS: Randomised, double-blind clinical trial in Brazil. Adults with pulmonary tuberculosis (PTB) and asymptomatic controls without known TB exposure or prior TB/TPT underwent C-TST, PPD RT-23, and QuantiFERON-TB Gold Plus (QFT-Plus). Skin tests were read by two strategies: (a) induration only or (b) induration or erythema, at a ≥5-mm cut-off. Sensitivity was assessed in PTB; specificity for C-TST and PPD RT-23 was estimated against QFT-Plus. Adverse events were monitored. RESULTS: Among 446 participants (141 PTB; 305 controls), at the 5-mm cut-off, C-TST showed lower sensitivity but higher specificity than PPD RT-23. With strategy (a) and (b), C-TST sensitivity was 0.67 and 0.68, specificity was 0.92 and 0.9, compared to 0.74 sensitivity and 0.78 specificity for PPD RT-23. Adverse events were more frequent in PTB: 12.1% (C-TST) and 6.4% (PPD RT-23); none were serious. CONCLUSION: In BCG‑vaccinated adults, C-TST showed a trade-off of higher specificity and lower sensitivity than PPD RT-23 at the 5-mm cut-off; and a favourable safety profile. Adding erythema to readings did not improve accuracy, suggesting that C-TST may be a useful alternative for programmatic TBI screening in high-burden settings. TRIAL REGISTRATION: Trial registry number RBR-7tn2ysw (https://ensaiosclinicos.gov.br/ registered on 25 January 2021).
Annals of medicineRuichao Feng, Yang Shao, Yuxin Zhao, Xiangfei Cui, Congcong Jiao, Hua Zhou
BACKGROUND: Given the established association between chronic kidney disease (CKD) and systemic inflammation, this study examined the relationships between complete blood count (CBC)-derived inflammatory markers and prevalent CKD. METHODS: Two data sets (Chinese clinical data, n = 4,518; NHANES 2017-2020, n = 7,724) are analyzed. Seven CBC‑derived inflammatory indices were calculated: SII, SIRI, NLR, dNLR, NMLR, MLR, and PLR. Each index was categorized into quartiles (Q1-Q4). Weighted logistic regression (for NHANES) and unweighted logistic regression (for the Chinese clinical data) were applied to estimate associations with CKD, with sequential adjustment for demographics, body mass index, and comorbidities. To control for multiple comparisons, false discovery rate (FDR) correction was applied. Furthermore, subgroup analysis, restricted cubic spline analysis and sensitivity analysis were also performed in this study. RESULTS: In the two fully adjusted models, the highest quartile (Q4) of SIRI, NLR, and NMLR was significantly associated with higher odds of prevalent CKD compared with Q1. After FDR correction, these associations remained significant in both cohorts: in the Chinese cohort, all padj < 0.001; in NHANES, padj = 0.028 for SIRI, 0.040 for NLR, and 0.041 for NMLR. Sensitivity analyses consistently supported the primary findings: excluding outliers, log2 transformation, and the alternative CKD definition yielded similar effect directions and significance levels. Heterogeneity was observed across subgroups, and restricted cubic splines revealed nonlinear dose‑response relationships (p for nonlinearity <0.05). CONCLUSIONS: Elevated SIRI, NLR, and NMLR are associated with prevalent CKD, suggesting systemic inflammation may play a role, yet prospective studies are required to establish temporality and causality.
BACKGROUND: Eosinophils are involved in the pathogenesis of atopic dermatitis (AD). OBJECTIVE: This post-hoc analysis evaluated the effect of stapokibart on blood eosinophil counts in moderate-to-severe AD patients. METHODS: The phase II AD002 trial (n = 120) randomly assigned patients to stapokibart 300 mg every 2 weeks (Q2W), 150 mg Q2W, or placebo for 16 weeks. The phase III AD005 trial (n = 500) randomly assigned patients to stapokibart 300 mg Q2W or placebo for 16 weeks, followed by open-label stapokibart 300 mg Q2W for 36 weeks. Efficacy and safety were analyzed in subgroups stratified by baseline blood eosinophil counts (≥500 or <500 cells/µL). RESULTS: Stapokibart treatment resulted in sustained reductions in blood eosinophil counts versus placebo (baseline vs. Week 16: high-dose 420 vs. 235 cells/μL, low-dose 530 vs. 315 cells/μL in AD002; 370 vs. 210 cells/μL in AD005). Furthermore, stapokibart demonstrated superior efficacy over placebo in achieving higher Eczema Area and Severity Index (EASI)-75 response rates at Week 16 in both eosinophil subgroups. The incidence of adverse events was similar across eosinophil subgroups, with most events being mild or moderate. CONCLUSION: Stapokibart reduced blood eosinophil counts in AD patients and demonstrated favorable efficacy and safety regardless of baseline blood eosinophil counts.
VirulenceYvette Kazungu, Shrilakshmi Hegde, Parul Sharma, Amy Marriott, Andrew Steven, Jesus Reine, Jessica Dagley, Matthias Mack, Anja Kipar, James P Stewart, Joseph D…
SARS-CoV2 can induce an acute respiratory distress syndrome (ARDS), provoked by a dysregulated hyper-inflammatory pulmonary immune response. Here, we used the keratinocyte-18 humanized angiotensin converting enzyme-2 (K18-hACE2) mouse model of SARS-CoV2, where expression of the CoV2 spike protein receptor, hACE-2, is restricted to epithelia, to characterize inflammatory pulmonary immune responses post-intranasal infections with the delta isolate SARS-CoV2(∆) B.1.617.2. Immune-profiling by focused transcript analysis, inflammatory protein array, and multi-color flow cytometry, confirmed that clinically relevant markers of COVID-19 (IL-6, GM-CSF, neutrophils, inflammatory monocytes) were significantly elevated in lungs of mice at day 5 post-infection and that remdesivir antiviral active metabolite (GS441524) treatment significantly modified SARS-CoV2∆ viral loads and pulmonary inflammation. Chemokine ligands of CCR2 (CCL2/7/8) were among the top 5% upregulated pulmonary transcripts in a focused human infection response array to SARS-CoV2∆. CCL2 was confirmed as elevated in protein assays in SARS-CoV2∆ infected lungs. To address the functional relevance of the CCR2 pathway of inflammatory cell recruitment to the lungs mediating disease, mice were administered with anti-CCR2 antibody daily at the point of infection for up to 6 d. Anti-CCR2 treated mice showed significant improved welfare scores, were protected from weight loss, modified myeloid pneumonitis, and displayed significantly blunted cytokine and chemokine response in the lungs, despite not affecting pulmonary viral loads. Our data supports therapeutic benefit of modifying CCR2-dependent cell recruitment in the treatment of viral-induced ARDS.
VirulenceYuying Zhang, Jiabao Xing, Hang Zhang, Jingchun Kong, Sue C Nang, Meng Zhang, Yushan Pan, Yajun Zhai, Li Yuan, Jinxin Zhao, Hua Wu
Acinetobacter baumannii AB5075 is a clinically relevant multidrug-resistant (MDR) isolate that poses a major therapeutic challenge. Although colistin has been reinstated as a last-resort antibiotic against MDR Gram-negative infections, the rapid emergence of colistin resistance threatens its clinical utility. Here, we employed a CRISPR-Cas9-based genome editing system to generate an A. baumannii AB5075 ΔrcnB mutant and uncovered a previously underappreciated role of rcnB in modulating colistin susceptibility. Loss of rcnB markedly potentiated colistin-mediated killing through multiple associated changes, including compromised membrane integrity, impaired oxidative stress defenses, and reduced efflux pump activity. Transcriptomic profiling further revealed that rcnB deletion reshaped global stress-response networks, including suppression of fatty acid biosynthesis and reactive oxygen species (ROS)-detoxifying pathways, alongside altered metal ion and sulfur metabolism during colistin exposure. Collectively, our findings suggest that rcnB may contribute to colistin susceptibility of colistin resistance and provide mechanistic insights that may inform the development of targeted strategies to enhance colistin efficacy against MDR A. baumannii.
Renal failureShuo Li, Yan Huang, Meiran Cao, Jingfu Wang
Background: The tubular atrophy/interstitial fibrosis (T) lesions of the Oxford Classification is a key prognostic determinant in IgA nephropathy (IgAN). The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is an emerging lipid marker, but its link with renal histologic damage in IgAN is unknown.Methods: This cross-sectional and retrospective study investigated the relationship between NHHR and T lesions in 400 biopsy-proven IgAN patients. Participants were divided into NHHR quartiles. The association between NHHR and T lesions was assessed using Spearman's rank correlation analysis, binary logistic regression analysis, restricted cubic spline (RCS) analysis, receiver operating characteristic (ROC) curve analysis, and subgroup analysis.Results: Compared to the lowest quartile (Q1), the highest NHHR quartile (Q4) showed significantly adverse clinical profiles and a higher prevalence of T1/T2 lesions (p < 0.05). NHHR was positively correlated with T lesions (r = 0.229, p < 0.001). Multivariate logistic regression analysis identified elevated NHHR and reduced estimated glomerular filtration rate (eGFR) as independent risk factors for T1/T2 lesions. RCS analysis demonstrated a linear association between NHHR and the risk of T1/T2 lesions (p for nonlinearity = 0.343). The ROC curve analysis yielded an area under the curve (AUC) of 0.635 for NHHR alone (optimal cutoff value = 3.54, sensitivity = 58.2%, specificity = 63.6%), and the composite NHHR+eGFR model achieved an AUC of 0.814. Subgroup analysis showed a consistent association between NHHR and the risk of T1/T2 lesions across all subgroups, with no significant interaction effects.Conclusion: Elevated NHHR is an independent risk factor for the progression of T lesions in patients with IgAN.
HIV research & clinical practiceHamzah M Alghzawi, Syed Zohad Shah, Zain Ul Abideen, Muhammad Farhan Ashraf
BACKGROUND: The combination of doravirine and islatravir (DOR/ISL) is a novel two-drug regimen for HIV-1. Early development faced challenges due to dose-dependent immunological signals. We aimed to synthesize the evidence on the efficacy and safety of DOR/ISL across all treatment-experience categories, specifically evaluating the impact of islatravir dosage (0.25 mg vs 0.75 mg) on clinical and immunological outcomes. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) following PRISMA guidelines. We searched PubMed, Embase, Cochrane Library, and Google Scholar from inception through April 2026. Primary outcomes were virological suppression (<50 copies/mL) and mean change in CD4+ T-cell count at week 48. Data were pooled using random-effects models. Islatravir dose was evaluated as a pre-specified moderator. Quality was assessed using Cochrane RoB 2.0 and certainty of evidence was graded using the GRADE approach. RESULTS: Seven RCTs (n = 3,600 participants) were included. At Week 48, DOR/ISL showed non-inferior suppression rates (RR 1.01 [95% CI 0.99-1.02]; p = 0.516; moderate-certainty evidence) and a statistically significant reduction in virological failure risk (RR 0.55 [0.33-0.92]; p = 0.022) compared to active control. Overall CD4+ gain was lower with DOR/ISL (MD -34.55 cells/μL; low-certainty evidence); however, a profound moderator effect of dose was observed (p < 0.0001). The 0.75 mg dose was associated with significant CD4+ and lymphocyte declines, whereas the approved 0.25 mg dose was immunologically neutral. DOR/ISL was weight-neutral compared to bictegravir/emtricitabine/tenofovir alafenamide (MD -0.25 kg [-0.66 to 0.16]; low-certainty evidence). CONCLUSION: DOR/ISL 100/0.25 mg once daily achieved virological suppression comparable to standard-of-care ART regimens and was associated with lower rates of virological failure compared with active comparators. The immunological safety concerns observed in early trials were successfully resolved by dose optimization. These findings support the use of DOR/ISL (IDVYNSO) as a potential treatment option for both treatment-naïve and virologically suppressed adults while emphasizing long-term safety surveillance.
Colorectal cancer (CRC) progression is driven by dynamic interactions among tumor cells, immune infiltrates, and the gut microbiota. While regulatory T cells (Tregs) may contribute to immune suppression in CRC, the role of non-conventional Tregs remains poorly defined. We identified a non-conventional population of microbiota-induced Tregs in the human colonic mucosa that co-expressed CD4, CD8α, CXCR6, and CCR6, termed DP8α Tregs, that exert potent immunomodulatory properties in different inflammatory settings. Their status and role in CRC, however, have not been investigated. Here, using multiparametric flow cytometry in a prospective cohort of CRC patients, we showed that DP8α Tregs are significantly enriched in tumors compared to paired non-tumoral colonic mucosa. Tumor-infiltrating DP8α Tregs displayed elevated expression of the CD39/CD73 ectonucleotidases, as well as CCR5, consistent with a suppressive phenotype within the tumor microenvironment. Functional co-culture assays further demonstrated that sorting DP8α Tregs from CRC tumors inhibited both CD4 and CD8 T-cell proliferation, an effect largely reversed by pharmacological inhibition of CD39 and CD73, which was associated with reduced IL-2 levels. Together, these findings show that DP8α Tregs enriched in the CRC tumor microenvironment, are able to suppress effector T-cell responses through the purinergic pathway and support further investigation of their contribution to immune regulation in CRC.
Food microbiologyHisaya K Ono, Tamako Kimura, Oku Okamoto, Yasunori Suzuki, Yusuke Sato'o, Taishi Tanabe, Dong-Liang Hu
Staphylococcus aureus in poultry is a potential source of food contamination and staphylococcal food poisoning. However, its carriage patterns and toxigenic potential at the slaughterhouse stage remain insufficiently characterized in Japan. This study investigated the prevalence and molecular characteristics of S. aureus in spent laying hens entering the processing line over a one-year period. Three anatomical sites (head, wing, and leg) were sampled per carcass (n = 800). S. aureus was detected in 649 of 800 birds (81.1%), and 995 isolates were obtained. Virulence gene profiling showed that 503 of 995 isolates (50.6%) carried one or more staphylococcal enterotoxin (SE) genes, with seh being the most prevalent, followed by sed and ser. se gene carriage was strongly site-dependent: isolates from the head and wing were predominantly se gene-positive, whereas most leg-derived isolates lacked these genes. Multilocus sequence typing of representative isolates revealed clonal heterogeneity, including newly registered sequence types with site-associated distributions. To assess toxigenic potential beyond gene carriage, we quantified production of selected enterotoxins in culture supernatants from broth cultures by enzyme-linked immunosorbent assay (ELISA) under different temperature conditions and further examined enterotoxin accumulation in chicken minced meat as a food-relevant matrix. In addition, SE accumulation above the detection limit was confirmed in chicken minced meat inoculated with a representative isolate under permissive temperature conditions (25 °C and 37 °C). These findings indicate that spent laying hens entering the processing line harbor S. aureus isolates from different anatomical sites with distinct virulence and toxigenic characteristics. The results provide baseline information on the microbiological status of birds at slaughterhouse entry and support the importance of temperature management during subsequent handling and processing to limit enterotoxin accumulation.
Food microbiologyJirapat Dawan, Yong Hyeok Yoo, Jin-Chul Kim, Sang Soo Lee
Staphylococcus aureus biofilms on stainless-steel surfaces show high tolerance to disinfectants, particularly in multidrug-resistant (MDR) strains, posing risks in food and pharmaceutical processing. Repurposing Generally Recognized as Safe (GRAS) compounds for low-dose biofilm control is therefore attractive. This study evaluated the antibacterial and antibiofilm efficacy and key mechanisms of mixed bile salt-weak base disinfectants against wild-type and MDR S. aureus biofilms. In brief, sodium cholate (CHO) and sodium chenodeoxycholate (CHE) were combined with ammonium hydroxide (AMH) or sodium bicarbonate (BIC) and tested against SA. ATCC and a multidrug-resistant SA. CCARM strains. Antibacterial activity and interactions were determined by minimum inhibitory concentration and checkerboard assays. Biofilms on sandblasted stainless-steel discs were assessed by viable cell counts, biofilm formation index, and extracellular DNA and polysaccharide levels. Transmission electron microscopy and quantitative real-time PCR of selected genes were used to examine structural damage and stress-response modulation. All preparations showed antibacterial activity, with higher MICs in the MDR strain. CHO + AMH displayed clear synergy against both strains, whereas CHE + BIC ranged from synergistic to additive. On stainless steel, CHO + AMH produced the greatest and most sustained reduction in biofilm-associated cells and the lowest biofilm formation indices, together with marked depletion of matrix components. TEM revealed extensive envelope disruption and cell damage under CHO + AMH compared with single agents. Combination treatments altered stress-response and efflux gene expression in patterns consistent with severe cellular injury and limited adaptive capacity. Accordingly, mixed bile salt-weak base disinfectants, particularly CHO + AMH, enhance antibacterial and antibiofilm activity against wild-type and MDR S. aureus by targeting cell envelopes, biofilm matrix, and stress-adaptation pathways. These GRAS-based combinations represent promising low-dose disinfectant candidates for controlling S. aureus biofilms on stainless-steel surfaces in processing environments.
The global spread of colistin (COL) resistance, particularly mediated by mcr-1, threatens the efficacy of this last-line antibiotic against multidrug-resistant (MDR) Gram-negative pathogens. This development underscores the urgency of developing innovative therapeutic strategies to counteract antimicrobial resistance mechanisms. This study demonstrates that piperine (PIP), a natural alkaloid, functions as a potent adjuvant that restores COL efficacy through a multi-target mechanism. The combination of PIP and COL exhibits significant synergism against clinically relevant pathogens, including mcr-1-positive strains (FICI: 0.07-0.281), and was not susceptible to the development of drug resistance. Additionally, this combination effectively inhibits and eradicates biofilms. Mechanism studies and omics analysis confirmed that PIP combined with COL could cause bacterial membrane disruption, proton motive force (PMF) disruption, efflux pumps inhibition, resulting in accumulation of bacterial reactive oxygen species (ROS) and finally cell death. Furthermore, PIP suppresses MCR-1 through dual suppression of gene expression and protein function. The therapeutic potential was confirmed in murine infection models, where the combination significantly improved survival rates, reduced bacterial loads, and attenuated inflammatory responses. This study provides the first comprehensive elucidation of the multi-target synergy between COL and PIP, offering a promising therapeutic strategy that simultaneously overcomes existing resistance and impedes resistance development.
Non-typhoidal Salmonella (NTS) is a leading bacterial pathogen responsible for foodborne outbreaks worldwide, with poultry products being a major source of human salmonellosis. While previous studies have predominantly focused on Salmonella transmission in the chicken production chain, ducks have received comparatively little attention as a potential reservoir host. In this study, we investigated Salmonella contamination across a commercial duck breeder-hatchery-grow-out (BHG) production system in Inner Mongolia, Hebei, and Shandong, China, comprising five breeder duck farms, one hatchery, and one commercial grow-out duck farm. From January 2022 to July 2025, a total of 7765 samples were collected across the duck BHG production system, from which 796 Salmonella isolates were recovered, yielding an overall prevalence of 10.25%. Serotyping analysis identified 16 serovars, dominated by S. Typhimurium (52.51%, 418/796), followed by S. Anatum (18.72%, 149/796) and S. Enteritidis (16.21%, 129/796). To further explore genomic relationships and potential transmission routes, 212 of the 418 S. Typhimurium isolates, representing diverse sampling time points, production stages, sample sources, locations, and antimicrobial-resistance profiles, were selected for whole-genome sequencing (WGS). Core-genome single nucleotide polymorphism (cgSNP) analysis revealed the presence of both vertical and horizontal transmission of S. Typhimurium from breeder ducks to commercial ducks. Antimicrobial susceptibility testing showed that 83 S. Typhimurium isolates (26.35%) exhibited antimicrobial resistance (AMR) to more than three classes of antibiotics. These isolates exhibited high resistance rates to ampicillin, amoxicillin, tetracycline, nalidixic acid, and streptomycin. A comparative genomic analysis of multidrug resistance genes identified an IS26-mediated chromosomal replacement event, leading to the replacement of a chromosomal region with a multidrug resistance region (MRR). This genomic rearrangement may contribute to the persistence and dissemination of multidrug-resistant clones within the production system. Overall, these findings demonstrate that Salmonella circulating in breeder ducks and farm environments can disseminate through eggs and the hatchery to commercial meat ducks, suggesting that the hatchery may serve as key points for amplification and cross-contamination. These results underscore the need for strengthened hatchery biosecurity, including routine surveillance, strict workflow separation, and enhanced cleaning and disinfection, to reduce the dissemination of antimicrobial-resistant Salmonella along the duck production chain.
Gut microbesMargaux de Seilhac, Margaux Verdon, Lucas Goisnard, Aurore Duquenoy, Nathalie Corvaia, Emilie Plantamura, Nicolas Lapaque, Fabienne Beguet-Crespel, Bastien Lap…
While the role of gut microbiota in health has been demonstrated, deciphering the involvement of individual bacterial species in diseases with unmet clinical needs represents a major research interest. Over the last decade, DP8α regulatory T cells (Tregs) have been identified to respond to Faecalibacterium duncaniae and protect against inflammatory bowel diseases (IBD) and acute graft-versus-host disease (aGvHD). To better understand, on the one hand, physiological DP8α Treg activation processes, and, on the other hand, the underlying mechanisms used by anti-inflammatory bacterial species to protect the host, we investigated whether additional key species could be recognized by DP8α Tregs. Here we showed that Blautia obeum, Roseburia intestinalis, and Akkermansia muciniphila indeed represent sources of antigens for DP8α Treg activation and priming, likely through their unique ability to induce tolerogenic antigen presenting cells. This study provides considerable mechanistic insight into the gut microbiota/regulatory T cell interplay and further establishes the role of DP8α Tregs, and their emerging dedicated ability to respond to gut microbiota, in local and systemic homeostasis.
Escalating resistance in Pseudomonas aeruginosa (PA) underscores the need for resistance-agnostic immunotherapies. In this study, we generated a panel of 20 monoclonal antibodies against the flagellin protein FliC and identified 16G10 as a high-affinity lead. Epitope mapping revealed a conserved linear site within the D1 domain (Gly71-Ile88), a region essential for filament assembly. In vitro, 16G10 induced bacterial aggregation, suppressed swimming motility, and significantly reduced adhesion to and invasion of A549 cells, while limiting biofilm biomass by SEM and confocal 3D imaging. In vivo, in murine pneumonia, where 16G10 administered either after pre-incubation with imipenem-resistant PA strain or as post-infection therapy, it improved survival, lowered lung bacterial loads, reduced IL-6 and TNF-α concentrations, and attenuated histologic inflammation. Protection extended across serotype A and B flagellated strains, indicating broad coverage. These data nominate 16G10 as a promising candidate for immunotherapy of drug-resistant PA lung infections and establish a druggable flagellin epitope for future vaccine and antibody designs.
Food microbiologyNatoavina T Faliarizao, Teresa M Bergholz, Kirk D Dolan
Dried chilies, although widely used as food ingredients such as paprika, present food safety risks across the production chain due to bacterial contamination, including Salmonella. This study assesses the fate of Salmonella Montevideo on red peppers during microwave drying and compares predictive models incorporating the effects of dynamic temperature and water activity (aw). Fresh red chilies (aw = 0.98) were sliced lengthwise, inoculated with Salmonella Montevideo, then dried at two power levels in a microwave oven for 45 min (120W) and 18 min (240W) to achieve aw<0.60. Temperature dynamics (24.5-87.6°C) were captured using an infrared camera, then the aw and Salmonella counts were measured at each sampling point. Salmonella survival parameters were estimated with four primary models (Weibull, log-linear, Geeraerd, and Cerf models), and then the Bigelow-type model was incorporated into the selected primary model to characterize the effects of temperature and aw on Salmonella inactivation. All models were assessed using the corrected Akaike information criterion (AICc). Higher microwave power resulted in lower Salmonella survival over time (p < 0.05) with a reduction range of 2.3-3.2 log. The log-linear/Bigelow (zT) yielded the lowest AICc value (11.94), which was the best-fitted model with D77°C-value of 4.24 min and a zT-value of 9.15°C. Temperature changes are determinant to describe Salmonella survival during chili drying, as the log-linear/Bigelow (zT) model better described the nonlinear reduction of Salmonella during the process. These findings serve as a basis to develop and refine spice drying conditions to improve Salmonella control while maintaining quality.
Bacillus cereus is a major foodborne pathogen characterized by robust biofilm formation and increasing antimicrobial resistance. This study identified 2-Methoxycinnamaldehyde (MCA) from Toona sinensis as the principal antibacterial compound and evaluated its inhibitory mechanisms and preservation potential. MCA exhibited potent activity against B. cereus ATCC 11778 (MIC = 150 μg/mL; MBC = 200 μg/mL) and resistant strains. In vitro assays demonstrated that MCA induced concentration-dependent membrane disruption, DNA damage, and intracellular protein leakage. Furthermore, treatment at 1 MIC and 2 MIC significantly impeded biofilm maturation; the secretion of extracellular proteins was reduced by 45.3% and 54.5%, polysaccharides by approximately 93%, and extracellular DNA (eDNA) by over 99%. Correspondingly, biofilm metabolic activity declined by 85.9% and 90.3%, and initial cellular adhesion was reduced by up to 88.1%. Untargeted metabolomic analysis revealed that these phenotypic defects stem from profound disturbances in amino acid biosynthesis, the TCA cycle, and nucleotide metabolism. Molecular docking revealed that MCA targets multiple essential bacterial enzymes, including ribonucleotide reductase, lysyl-tRNA synthetase, pyruvate kinase, betaine aldehyde dehydrogenase, and 5'-nucleotidase, through stable hydrogen bonding and π-interactions. In a refrigerated pork model, MCA completely eliminated B. cereus by day 7 while significantly delaying pH increases and color deterioration. These findings provide the first evidence for MCA as an antibacterial and antibiofilm agent against B. cereus, highlighting its potential in food preservation.