Exposure to Mycobacterium tuberculosis (Mtb) leads to a spectrum of outcomes, from latent infection to active disease, but limited insight into protective immune correlates has hampered vaccine development. Using a proteome-wide Mtb microarray, we mapped antibody specificities across individuals with varying Mtb exposure, including humans with controlled latent tuberculosis infection, uncontrolled active TB, or that resist IGRA conversion as well as non-human primates with near sterilized Mtb infection following intravenous BCG. While current TB vaccine antigens were poorly immunogenic across most populations, striking overlap in antibody binding was observed to surface and secreted proteins, all associated with enhanced antibody functions and some also robustly targeted by T cells. Collectively, these data provide an atlas of antibody protein binding across the spectrum of Mtb infection, and further point to a handful of promising Mtb protein candidates to guide the design of antibody-based TB interventions aimed at mitigating disease globally.
Antimicrobial resistance (AMR) is a global public health threat. Mortality and poor treatment outcomes are the key consequences of AMR. Conventional antimicrobial susceptibility testing (AST) is slow, limited in coverage, and dependent on laboratory infrastructure, creating delays in clinical decision-making. In this study, we developed a hybrid deep learning model for broad-spectrum antimicrobial resistance prediction by analyzing 699 bacterial genome assemblies and paired antimicrobial susceptibility outcomes across 22 antibiotics. Genome assemblies were encoded using 6-mer frequency and antimicrobial susceptibility phenotypes were engineered into genome-antibiotic pairs for binary prediction. The proposed model integrates convolutional neural networks (CNNs) for local sequence feature extraction, bidirectional long short-term memory (BiLSTM) networks to capture long-range genomic dependencies, and an attention mechanism to improve interpretability. Model evaluation achieved an accuracy of 0.772 and AUROC of 0.77 at a resistance decision threshold of 0.55, with balanced accuracy of 0.697 and AUPRC of 0.489. The results demonstrate variable predictive performance across antibiotics and organism groups. This study demonstrates that a hybrid CNN-BiLSTM-Attention model can rapidly predict antimicrobial resistance from genome-derived k-mer features while incorporating organism and antibiotic metadata for broad-spectrum AST prediction. This framework offers a scalable way to predict susceptibility from genome data and can help advance the development of AMR decision-support tools for clinical use.
The frequency of central nervous system (CNS) fungal infections is rising, leading to increased mortality. These infections pose diagnostic challenges, and therapy depends on the specific fungal pathogen identified. Only a few studies from India have examined the spectrum of fungal pathogens causing CNS infections. The objective of this study was to analyze the clinical and microbiological diversity of fungal pathogens responsible for CNS infections. This was a retrospective study conducted at a tertiary care center in India from January 2023 to December 2024. The study included patients in whom fungi were isolated from cerebrospinal fluid, brain abscess pus, and paraspinal abscesses. Nine fungal pathogens were identified during the study period. Three isolates were yeasts and six were molds. Brain abscess was the predominant clinical presentation. The yeast isolates included Cryptococcus neoformans (n = 1) in meningitis and Candida tropicalis (n = 1) and Candida parapsilosis (n = 1) in VP shunt infections. The molds isolated from brain abscesses included Cladophialophora bantiana (n = 1), Rhizopus arrhizus (n = 1), Aspergillus flavus (n = 2), Scedosporium apiospermum (n = 1), and Chaetomium lucknowensis (n = 1). Mortality was observed in 4 of 9 cases (44.4%). In the present study, nine fungal pathogens were isolated over a two-year period from varied clinical presentations. This highlights the rarity of the condition, which should not be overlooked.
The rapid emergence of multidrug resistant Enterobacterales, especially extended-spectrum β-lactamase (ESBL)-producing strains, poses a significant One Health challenge in low- and middle-income countries, including Bangladesh. This study aimed to investigate the prevalence, antimicrobial resistance patterns, and resistant genes profile of Escherichia coli and Klebsiella pneumoniae isolated from quails in the Sylhet district of Bangladesh. A cross-sectional study was conducted with 404 cloacal swabs were collected from quails across multiple retail locations. Isolates were identified using culture, biochemical tests, and PCR. Antimicrobial susceptibility was assessed by the Kirby-Bauer disk diffusion method against 12 antibiotics. Resistance and virulence genes, including stx1, tetA, strA, AAC(3)-iv, sul1, and β-lactamase genes, were detected using multiplex and monoplex PCR. Multiple antibiotic resistance index (MARI) and MDR status were determined. E. coli was detected in 63.37% (256/404) of samples, of which 53.91% were Shiga toxin-producing (stx1). K. pneumoniae was confirmed in 11.14% (45) of isolates. Both organisms showed 100% resistance to ampicillin and amoxicillin-clavulanic acid. Nearly all isolates were multidrug resistant, with mean MARI values of 0.58 for E. coli and 0.48 for K. pneumoniae. High frequencies of resistance genes were observed, with strong phenotype-genotype alignment. In K. pneumoniae, the blaTEM (65.96%), MulticaseMOX (44.68%) and MulticaseDHA (10.63%) genes predominated. Overall, the findings highlight quails in Bangladesh as an important and previously under recognized reservoir of multidrug resistant E. coli and K. pneumoniae, underscoring the urgent need for strengthened antimicrobial stewardship and One Health based surveillance strategies.
Early diagnosis of invasive fungal diseases (IFD) remains a major clinical challenge due to pathogen diversity and nonspecific symptoms. This study used metagenomic next-generation sequencing (mNGS) technology to comprehensively characterize fungal profiles across various clinical specimens and the demographic characteristics (sex and age) of the patient population. The results provide laboratory evidence to support the diagnosis and treatment of fungal infections. A total of 11,161 mNGS reports from clinical specimens collected at the Renmin Hospital of Wuhan University between March 2022 to August 2024 were retrospectively analyzed. Fungal spectra and patient demographics were comprehensively profiled and compared across different specimen types. The highest fungal detection rate was observed in bronchoalveolar lavage fluid (36.85%, 1,985/5,387), followed by urine (22.76%, 264/1,160), blood (13.38%, 380/2,840), pleural and peritoneal fluid (12.91%, 174/1,348), cerebrospinal fluid (CSF) (13.82%, 17/123), and wound exudates (12.87%, 39/303). Candida species were the most frequently detected fungi across all specimen types except CSF, wherein Aspergillus predominated. Overall fungal detection rates were significantly higher in male patients than in female patients (26.76% vs. 23.84%, P < 0.01) and in individuals aged > 60 years compared with those aged ≤ 60 years (33.04% vs. 20.02%, P < 0.001), although this trend varied by specimen type. Multivariate logistic regression analysis confirmed that male sex (adjusted odds ratio [aOR]=0.893,95% confidence interval: 0.824-0.967, P = 0.006) and advanced age (≥80 years: aOR=14.77,95% confidence interval: 12.08-18.06, compared with minors) were independent risk factors for fungal detection. Among fungal-positive specimens, 68.28% (1,952/2,859) were co-detected with bacteria, and 15.63% (447/2,859) showed polyfungal detection (≥ 2 fungal species). In conclusion, our findings highlight the predominance of Candida and Aspergillus, identify elderly male patients as a high-risk population, and underscore the high frequency of bacterial-fungal co-detection. Overall, Clinicians should combine mNGS results with imaging, conventional fungal tests (G/GM assays, culture), and clinical presentation for a more accurate diagnosis of IFD.
The urgent need for novel antimicrobial agents arises from the escalating threat of antibiotic-resistant pathogens. Tackling the resistance mechanisms through the application of resistance modifying agents in combination to antimicrobials represents an effective strategy to combat antimicrobial resistance and to enhance the antimicrobial activity. Screening of plant extracts, essential oils and their active compounds for potential resistance modifying properties has proven effective on both a small and large scale. In this study, we define the metabolomic profile of essential oils extracted from different parts of Cymbopogon citratus (DC.) Stapf (lemongrass), and characterize their antioxidant and virulence attenuating activities. The major active ingredients of essential oils extracted from different parts of Cymbopogon citratus (lemongrass) were identified by GC-MS analysis. The minimum inhibitory concentration (MIC) of the essential oils against P. aeruginosa PAO1, Staphylococcus aureus ATCC 6538, and Candida albicans ATCC 10,261 was determined using the broth microdilution assay. Antibiofilm and antiprotease activities were phenotypically evaluated for the extracted lemongrass essential oils for the same standard strains and clinical isolates for the same microbes. Also, the effects on microbial virulence were validated by RT-qPCR against a subset of genes regulating biofilm, quorum sensing, and stress response in P. aeruginosa, and S. aureus. Furthermore, the antioxidant activities of the different essential oils extracted were evaluated using DPPH, β-carotene/linoleic acid and FRAP methods. GC-MS analysis of the essential oils of Cymbopogon citratus revealed the presence of 47 different compounds distributed in the different plant organs. Active constituents such as geranial, neral, myrcene, nerolic acid, linalool, iso-citral, trans iso-citral, and neryl acetate were more abundant in the essential oil extracted from leaves (89.77%), followed by stems (82.92%) and finally roots (52.02%). S. aureus, and C. albicans were more sensitive to C. citratus essential oils than Gram negative P. aeruginosa. Incorporation of sub-MIC doses of essential oils into the culture media was sufficient to disrupt the formation of microbial biofilms in P. aeruginosa, S. aureus, and C. albicans, and to inactivate the proteolytic activities of microbial proteases. The essential oils of C. citratus showed promising and broad-spectrum biofilm eradicating activity. Sub-MIC doses of lemongrass oil dramatically reduced the expression of relA, pslA, and spoT in P. aeruginosa, and agrA, icaA, and sigB in S. aureus indicating a broad-spectrum anti-virulence activity. Our study identifies C. citratus essential oils as potential virulence-attenuating agents. Essential oils extracted from the leaves, stems, and roots of C. citratus exhibited significant antimicrobial, anti-biofilm, anti-virulence, and antioxidant activities, effectively combating microbial resistance. These findings suggest that C. citratus essential oils could be a valuable natural alternative in the fight against resistant pathogens.
Quantification of prescription of antimicrobial agents and use of paediatric outpatient services before, during and after the COVID-19 pandemic. We conducted a population-based study using Norwegian linked health registries and Japanese claims (2018-2023). Paediatric antibiotic prescription rates, broad-spectrum use, and proportion of antibiotic prescriptions with prior presumed bacterial infection diagnoses were analysed monthly, overall and by age groups and sex. Interrupted time series analyses were performed to evaluate pandemic-related changes, expressed in rate ratio (RR) and its CI, using March 2020 as the interruption point and the pre-pandemic trend/level as reference. Data on 5.5 million children and 19.5 million antibiotic prescriptions were analysed. Before the pandemic, antibiotic prescribing was higher in Japan (120-200/1000 children/month) than in Norway (10-20/1000). At pandemic onset, rates fell by 45% in Norway (RR = 0.55; 95% CI, 0.45-0.67) and by 53% in Japan (RR = 0.47; 95% CI, 0.41-0.55), then by 2023 had returned to expected levels. Broad-spectrum antibiotic use was much higher in Japan (70%) compared with Norway (10%) before the pandemic. However, Norway experienced a sharp 20% increase whereas Japan remained largely unchanged post-pandemic. The proportion of prescriptions with a prior presumed bacterial diagnosis was between 50% and 65% before the pandemic then decreased modestly by 5%-10% at pandemic onset, followed by gradual rebound in both countries. The COVID-19 pandemic significantly altered paediatric antibiotic prescribing in both countries. Sustained antibiotic stewardship efforts are needed to ensure appropriate paediatric antibiotic use in the post-pandemic era.
Viral infections trigger complex host defense responses, yet many key regulatory mechanisms remain undefined. Here, we identify the RNA-binding protein RBM25 as a potent, broad-spectrum host antiviral factor, independently of the type I interferon (IFN-I) pathway. Viral infection downregulates RBM25 expression, and RBM25-deficient mice exhibit enhanced susceptibility to multiple viruses and more aggravated tissue damage. In vitro, RBM25 inhibits the viral infection and replication across a spectrum of RNA and DNA viruses. Mechanistically, the antiviral activity of RBM25 is independent of IFN-I signaling and is instead linked to an early blockade in the viral life cycle. RBM25 specifically impedes viral cell entry through the suppression of the host GTPase Rab22a, a well-known facilitator of viral endocytosis. Virus infection-elicited downregulation of RBM25 results in Rab22a upregulation, which consequently potentiates viral entry. Furthermore, we elucidate the post-transcriptional mechanisms that RBM25 interacts with RC3H1 (ring finger and CCCH-type domains 1) to form an RNA-binding complex that binds and destabilizes Rab22a mRNA, thereby limiting its protein translation. Collectively, our work unveils the RBM25/RC3H1-Rab22a axis as an interferon-independent post-transcriptional pathway that governs viral entry by modulating the mRNA stability of a critical host endocytosis factor, which presents a potential target for developing broad-spectrum antiviral strategies.
Multiplex polymerase chain reaction (PCR) assays have transformed the diagnosis of infectious gastroenteritis by enabling rapid, simultaneous detection of multiple enteric pathogens. However, contemporary data describing pathogen distribution, age-specific patterns, co-infection, and seasonality in Saudi Arabia remain limited. This study aimed to characterize the epidemiology of gastrointestinal pathogens detected by multiplex PCR in a tertiary care center in Riyadh, Saudi Arabia. We conducted a retrospective analysis of stool specimens tested using a multiplex gastrointestinal PCR panel at King Abdulaziz Medical City, Riyadh, between January 2023 and December 2024. Demographic data, detected pathogens, co-infection status, and timing of testing were analyzed. Repeat samples from the same patient within 30 days were excluded. Descriptive analyses assessed pathogen distribution by age group and season, and multivariable logistic regression was used to identify factors independently associated with co-infection. Of 9,122 stool specimens processed, 2,866 positive tests from 2,189 unique patients remained after excluding 30-day repeat samples. Positivity was 31.4%, higher in pediatrics than adult patients (36.5% vs. 28.0%, p < 0.001). The most frequently detected pathogens were Clostridioides difficile toxin A/B, enteropathogenic Escherichia coli, enteroaggregative E. coli, norovirus, and Salmonella spp. Co-infections occurred in 30.8% of positive samples, more commonly in pediatric patients. In multivariable analysis, children under 2 years had significantly higher adjusted odds of co-infection compared with adults aged 18-64 years, and source of sample was independently associated with co-infection. Multiplex PCR testing revealed a diverse, age-dependent spectrum of gastrointestinal pathogens with a substantial burden of co-infections. These findings highlight the importance of age-specific interpretation and careful clinical correlation of multiplex PCR results.
Cribriform morular thyroid carcinoma (CMTC) is a rare neoplasm more common in young euthyroid females, usually associated with familial adenomatous polyposis (FAP) syndrome, but also presenting as sporadic cases. These tumors result from the activation of the WNT/β-catenin signaling pathway, usually through germline APC gene mutations in FAP-associated disease, while sporadic cases may exhibit somatic mutations in APC, CTNNB1, and AXIN1. Additional possible molecular events include somatic mutations in KRAS, PIK3CA, KMT2C, KMT2D, TERT promoter or RET rearrangements. BRAF mutations do not occur. We describe a sporadic case of high-grade CMTC presented in a 44-year-old female with a large multilobulated, unifocal mass in the right thyroid lobe. The tumor showed the typical cribriform and morular patterns, high grade features (Ki-67 proliferative index of 20% and foci of necrosis), marked vascular invasion and regional lymph node metastases. The tumor cells were immunoreactive for keratin (KRT) clone CKAE1/AE3, KRT7, and TTF1/NKX2, with aberrant (nuclear and cytoplasmic) expression of β-catenin, but negative for thyroglobulin and calcitonin. CDX2 was detected exclusively in the morular structures. The somatic APC p.(Thr621Leufs*9) oncogenic variant and the somatic TERT promoter - 124 (C228T) oncogenic variant were found, in line with the tumor type and tumor grade respectively; but, for the first time, EWSR1 gene rearrangement was also detected, expanding the molecular spectrum of this uncommon entity.
To evaluate the in-vitro activity of cefepime-enmetazobactam (FEP-EMT)-a novel β-lactam-β-lactamase inhibitor (BL/BLI) combination against Extended-spectrum β-lactamase (ESBL)- and AmpC β-lactamase (AmpC)- producing Enterobacterales isolated from diverse clinical samples. To compare efficacy of FEP-EMT against other BL/BLIs and assess its use as a potential carbapenem sparing option. A prospective laboratory study was conducted and 147 clinically significant nonrepetitive ESBL- and/or AmpC-producing Enterobacterales isolated from various clinical samples were included. The zone diameter for FEP-EMT was determined by Kirby-Bauer disk diffusion method and interpreted according to the EUCAST July 2024 guidelines. The susceptibility to other antibiotics, was noted as per CLSI 2025, with special emphasis to BL/BLIs. Between January 2025 and September 2025, 147 ESBL- and/or AmpC-producing isolates were collected from clinically relevant specimens. Escherichia coli (106, 72.1%) was the most predominant isolate, followed by Klebsiella pneumoniae (32, 21.8%). Among the 147 isolates, 95.2% were susceptible to FEP-EMT compared to 88.7%, 73.4% and 63.0% susceptibility to cefaperazone-sulbactam, piperacillin-tazobactam and amoxicillin-clavulanic acid respectively. Notably, all FEP-EMT (7/147) resistant isolates demonstrated resistance to these BL/BLI combinations. FEP-EMT restored susceptibility to cefepime in 97.8% isolates. FEP-EMT demonstrated good activity in Enterobacterales demonstrating multiple resistance mechanisms to third generation cephalosporins. Cefepime-enmetazobactam showed higher or comparable in vitro activity against ESBL- and/or AmpC-producing Enterobacterales compared to conventional BL/BLI options. Hence, it can serve as an effective alternative treatment for resistant pathogens.
Antimicrobial resistance and persistent biofilm-associated infections continue to drive the search for peptide-based anti-infective agents with mechanisms distinct from conventional antibiotics. Killer Peptide (KP) is an antibody-derived decapeptide originally identified through yeast killer toxin mimicry studies and has emerged as a distinctive example of a multifunctional bioactive peptide. Experimental studies have reported particularly strong antifungal activity, together with activity against selected bacteria, biofilms, viruses, and protozoa, as well as immunomodulatory effects in preclinical models. Mechanistically, KP appears to act through a multistep process involving target-surface recognition, cellular internalization, induction of intracellular stress pathways, and reversible self-assembly into fibrillar structures that may support localized peptide retention. In parallel, KP has been reported to influence innate and adaptive immune responses, suggesting potential host-defense-enhancing properties. In this review, we critically reassess two decades of KP research, covering its molecular origin, structural features, antimicrobial spectrum, mechanisms of action, engineered derivatives, and translational prospects. We also examine current limitations, including the relatively narrow evidence base, incomplete pharmacological characterization, and the need for independent validation across disease models. KP represents a useful conceptual framework for the development of next-generation multifunctional peptides integrating antimicrobial, pathogen-triggered assembly, and immunomodulatory properties.
Inherited retinal diseases (IRDs) may present as an isolated ocular condition or as part of multisystem disorders, such as Bardet-Biedl syndrome (BBS). Several BBS-related manifestations are age-dependent and variably expressed. Therefore, patients with early or subtle extra-ocular features may be incorrectly diagnosed as having non-syndromic IRD. There are two diagnostic frameworks for BBS: a phenotype-based, Beales-derived approach and a genotype-first approach, as recommended by the InterEuropean Reference Networks (ERNs) criteria. Here, we aimed to conduct comprehensive evaluations of patients with IRD carrying BBS-related variants. Nineteen patients from nine Jordanian families initially diagnosed with non-syndromic IRD underwent detailed ophthalmic evaluation and molecular testing. Post-genetic testing, participants underwent targeted reverse phenotyping to reveal potentially overlooked syndromic features. Ophthalmic assessment revealed a spectrum ranging from advanced IRDs to phenotypes inclining toward rod-cone, cone-rod, and macular dystrophies. Molecular testing identified potential causative variants in BBS-related genes known to cause both isolated IRD and BBS, namely, CFAP418, BBS2, BBS1, BBS5, and CEP290. A splice donor variant in CFAP418 was the most frequent in our cohort (numbers [n] = 3/9 families), followed by a missense variant in BBS2 (n = 2/9 families). These findings prompted genotype-guided reverse phenotyping, which uncovered previously unrecognized multisystemic involvement. BBS-related major and minor features were discovered across the cohort. The extraretinal major features included obesity (n = 16 patients), polydactyly (n = 7 patients), renal anomalies (n = 7 patients), genitourinary abnormalities (n = 4 patients), and intellectual disability (n = 4 patients). Using Beales-derived criteria, 11 patients met the threshold for BBS. Under ERNs genotype-first recommendations, 18 patients reached the BBS diagnostic limit. Wide intra- and inter-familial clinical variability was observed, even among patients with the same variants in CFAP418 and BBS2. Furthermore, applying genotype-guided diagnostic criteria reclassified multiple patients who did not meet the traditional Beales-based clinical criteria as having BBS. These findings demonstrate that a genotype-first approach can detect patients with unrecognized BBS and facilitate appropriate clinical surveillance, genetic counseling, and management. To our knowledge, this is the first study from Jordan to integrate molecular testing with reverse phenotyping in patients carrying BBS-related genotypes. Importantly, we present the most comprehensive extra-retinal characterization of patients with CFAP418, so far.
To determine whether carbapenem overuse affects clinical outcomes in children with susceptible Escherichia coli (E. coli) bloodstream infection (BSI) using propensity score matching (PSM). We conducted a retrospective study of 206 pediatric patients with E. coli BSI. This study evaluated the appropriateness of empirical antibiotic therapy (initiated before blood culture results), retrospectively judged by subsequent susceptibility testing. Patients were categorized into a standard-therapy group (n=123) and an inappropriate carbapenem therapy group (n=83). One-to-one PSM generated 67 matched pairs with balanced baseline characteristics. Standard logistic regression was adopted for correlation analyses before matching, while conditional logistic regression was used to explore risk associations with mortality, sepsis and septic shock after matching. After PSM, all covariates were balanced (standardized mean differences <0.2). Overall mortality was 10.68%. No significant differences were observed between the inappropriate carbapenem group and the standard therapy group regarding mortality, sepsis, septic shock, or duration of hospitalization, in both unmatched and matched analyses. In the matched cohort, no significant associations were observed for mortality (OR 0.75, 95% CI 0.26-2.16, p= 0.594), sepsis (OR 0.93, 95% CI 0.44-1.98, p=0.847), septic shock (OR 0.83, 95% CI 0.25-2.73, p=0.776). Likewise, no significant between-group difference in duration of hospitalization was detected via the paired Wilcoxon signed-rank test (p = 0.777). No significant differences in mortality, sepsis, septic shock, or duration of hospitalization were observed between the inappropriate carbapenem group and the standard therapy group. These findings reinforce the importance of antimicrobial stewardship by demonstrating that initial narrow-spectrum therapy (third-generation cephalosporins) achieves comparable outcomes, thereby reducing unnecessary carbapenem exposure.
Root rot is a very destructive soil-borne disease severely affecting the quality and yield of common name Angelica sinensis in its main production region (Gansu Province, China). Here, a new Trichoderma asperellum strain M2 with broad-spectrum antifungal activity was assessed for its biocontrol effects against Angelica root rot. This fungal strain produces various hydrolases enzymes, notably cellulase (highest activity), and secreted 12.8 mg/L of indole-3-acetic acid (IAA) in a medium enriched with tryptophan. Scanning electron microscopy showed that M2's mycelium surrounded or parasitized the pathogen's mycelium, leading to the pathogens hyphae collapse, morphological fracture, and shrinkage. Pathogenicity test confirmed that M2 had significant control effect against Fusarium acuminatum, with its prior inoculation being more effective (maximal inhibition rate: 57.61%). Compared with the control, treatment with strain M2 significantly increased the plant height, root length, fresh weight, and dry weight of A. sinensis seedlings by 30.2%, 67.0%, 33.5%, and 61.8%, respectively, while also increasing their enzyme activity for catalase (CAT), phenylalanine ammonia-lyase (PAL), peroxidase (POD), and polyphenol oxidase (PPO) by 12.82, 0.52, 1.57, and 3.7 times, respectively. A fermentation broth of strain M2 was highly effectively at degrading the neosolaniol (NEO) toxin, achieving a remarkable degradation rate of 87.14% after 11 days of treatment. Degradation ratios of the active cell component (49.40%) and extracellular component (33.6%) both significantly exceeded that of the intracellular component (24.2%), suggesting NEO removal mainly via biodegradation. Four products were identified by liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS) for NEO's degradation by the strain M2. This study's findings provide a fresh perspective and strategy for applying multi-functional T. asperellum M2 to the biological control of Angelica root rot.
Streptococcus pneumoniae is an opportunistic respiratory commensal bacterium and leading cause of pneumonia, meningitis, and sepsis, resulting in over a million deaths annually, particularly in children aged under 5. The rapid spread of macrolide-resistant strains led the WHO to designate S. pneumoniae as a priority pathogen that urgently requires alternative therapeutic strategies. Here, we identified the FDA-approved cancer drug sorafenib to show a dose-dependent, broad-spectrum efficacy against many pneumococcal serotypes, including multidrug-resistant clinical strains. In silico screening and molecular dynamics simulations indicated potential interaction with the catalytic cleft of the pneumococcal serine/threonine kinase StkP, a central regulator of cell division and peptidoglycan synthesis. In vitro kinase assays using purified recombinant StkP kinase domain and p-Thr-specific immunoblotting revealed dose-dependent inhibition of kinase activity by sorafenib in pneumococci. Ectopic expression of StkP partially rescued growth inhibition by sorafenib, and the direct interaction was assessed by isothermal titration calorimetry, suggesting StkP as one of the potential targets in S. pneumoniae. Sorafenib-treated bacteria showed abnormal morphology, increased membrane permeability, enhanced complement C3 deposition, and reduced adherence and invasion into lung epithelial cells without significant host cytotoxicity. Serial passaging of bacteria in vitro with sorafenib suggested low resistance potential. In vivo, sorafenib administration at 10% of the clinically relevant dose delayed mortality and significantly reduced bacterial burden in a murine pneumonia model, supporting its further preclinical development for therapeutic intervention. Streptococcus pneumoniae, a WHO priority pathogen and causative of pneumonia, meningitis, and sepsis worldwide, has developed resistance to several commonly used antibiotics, limiting available treatment options. In this study, we show that sorafenib, a drug currently approved for cancer treatment, can also inhibit the growth and disease-causing ability of S. pneumoniae, including clinical strains. Our findings reveal that sorafenib interferes with a key bacterial regulatory enzyme that controls cell division and cell wall formation, exposing a previously underexplored vulnerability in this pathogen. Because sorafenib is already clinically approved, this work highlights the potential of drug repurposing as a faster route to identify new antimicrobial therapies. More broadly, our results demonstrate that bacterial kinases represent promising targets for developing next-generation treatments against key bacterial pathogens.
The coastal waters of Bangladesh support rich aquatic biodiversity, including the commercially important shrimp Penaeus monodon. However, antimicrobial resistance (AMR) poses a growing threat to aquaculture, ecosystem stability, and human health. In this study, we investigated bacterial AMR profiles and characterized the gut microbiomes of wild (Natural) and cultured P. monodon from the northern Bay of Bengal, Bangladesh. Culture-based and biochemical methods were used to identify bacterial pathogens of shrimp shells, and antimicrobial susceptibility was assessed using the disc diffusion method. Shotgun metagenomic sequencing was used to characterize gut microbial diversity and identify antibiotic resistance genes (ARGs). All Klebsiella isolates were resistant to ampicillin (100%) and showed high resistance to azithromycin (83%) and nitrofurantoin (73%). Pseudomonas isolates were 93.10% resistant to ampicillin, whereas Vibrio isolates had notable resistance to azithromycin (71.05%) and colistin (63.16%). Metagenomic analysis revealed comparable alpha diversity between wild and cultured shrimp, with Vibrio being predominant in both groups and V. parahaemolyticus as the most abundant species. Cultured shrimp harbored greater microbial diversity, including additional genera such as Shewanella, Lactococcus, and Enterobacter. A total of 30 ARGs were detected, primarily associated with β-lactams and tetracycline resistance. Cultured shrimp exhibited a broader ARG spectrum, reflecting potential anthropogenic impacts on aquaculture practices. These findings suggest that cultured shrimp environments can serve as reservoirs of resistant bacteria and ARGs. Therefore, improved antimicrobial stewardship and regular monitoring are essential to curb the spread of AMRs in marine ecosystems.
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus associated with a broad spectrum of malignancies and immune-mediated disorders, and growing evidence highlights the importance of host glycan-lectin interactions in shaping viral persistence and immune escape. Among these, galectins have emerged as key regulators of the EBV life cycle, influencing viral attachment, latency maintenance, lytic reactivation, and the remodeling of the tumor microenvironment. Galectin-1, -3, and -9 exhibit context-dependent functions that collectively modulate oncogenic signaling pathways, T‑cell exhaustion, regulatory T‑cell expansion, and innate immune sensing. Recent clinical studies further suggest that circulating galectins and galectin-enriched exosomes may serve as non-invasive biomarkers for disease progression and prognosis in EBV-associated malignancies. Despite these advances, major knowledge gaps remain regarding member-specific functions, compensatory galectin networks, and the spatiotemporal dynamics of galectin regulation during infection. Targeting the galectin-glycan axis therefore represents a promising frontier for host-directed antiviral and anticancer therapies, with the potential to disrupt viral latency, restore antiviral immunity, and improve clinical outcomes in EBV-driven diseases.
Extended-spectrum β-lactamase-(ESBL)-producing Enterobacteriaceae are emerging in hospital and community settings as important causes of urinary tract infections. These plasmid-mediated enzymes have been identified in human and dog hosts, with blaCTX-M variants being the most prevalent ESBLs worldwide. Our objective was to identify horizontal gene transfer (HGT) events amongst human and dog-derived ESBL-producing bacteria by examining genetic relatedness of plasmid and bacterial whole genome sequences (WGS) associated with ESBLs and other β-lactamase genes. By understanding genetic relatedness, we aimed to provide insight into transmission dynamics of ESBLs and antibiotic resistance among humans and dogs in community-acquired settings. Of 149 plasmids collected from humans (n = 125) and dogs (n = 24), 111 (74.5%) carried class A ESBL genes with blaCTX-M-14 (31.6%) predominating in human-derived plasmids and blaCTX-M-1 in dog-derived plasmids (29.6%). In addition, ESBLs and other β-lactamase genes, including blaTEM-1,were also identified in both populations. pMLST showed that IncF, IncI1, and IncN plasmids were the main groups contributing to the dissemination of ESBLs amongst human and dog populations. Neighbor-joining analysis revealed clustering of human and dog-derived plasmids carrying similar ESBL genes as well as other antibiotic-resistant genes. The maximum-likelihood tree revealed a high predominance of ST131 carried by E. coli serotypes O25:H4 in humans but not dogs. Virulence gene analysis revealed that ESBL-producing bacteria were not limited to UPEC. The presence of conserved ESBLs, other β-lactamase genes and E. coli clones in both humans and dogs highlights widespread circulation of shared resistance elements. These findings support the need for broader One Health surveillance, particularly involving companion animals, to better track and mitigate ARG spread in community settings.
Nodular granulomatous phlebitis is an exceptionally rare and probably underdiagnosed form of tuberculid. It is characterized by granulomatous inflammation centered on the walls of subcutaneous veins and may clinically mimic panniculitis or superficial thrombophlebitis. We report a new case of this entity together with a comprehensive review of the literature to better delineate its clinical and histopathologic spectrum. This is a poorly recognized tuberculid in which histopathologic findings are essential for establishing the diagnosis. Awareness of this pattern is particularly important for both dermatologists and pathologists, because failure to recognize it may lead to inappropriate immunosuppressive treatment and the consequent risk of reactivation of latent tuberculosis.