Search Results (4,685)

Multicomponent antibiotic–anti-inflammatory systems have recently attracted considerable attention, as this combination is becoming a standard therapy for infectious diseases. This study aimed to develop a multicomponent system comprising norfloxacin (NOR), an old fluoroquinolone antibiotic, and niflumic acid (NIF), another old, poorly soluble anti-inflammatory drug, to improve the physicochemical properties, antibiotic potency, and anti-inflammation effect, as well as their safety. First, a phase diagram was constructed to ensure solid-state reaction and to predict its stoichiometry; subsequently, the multicomponent system was prepared by solvent-drop grinding. The product was analyzed by a series of thermal analyses and powder X-ray diffraction (PXRD). Next, Fourier-transform infrared spectroscopy and nuclear magnetic resonance elucidated the molecular interactions, and the final 3D structure was determined by single-crystal X-ray diffraction, followed by Hirshfeld surface analysis. Afterward, the solubility and chemical stability were assessed using high-performance liquid chromatography, and the physical stability of the multicomponent system was evaluated by PXRD. Antimicrobial potency against Gram-negative and Gram-positive bacteria, as well as anti-inflammatory activity in vivo, were also evaluated. The results demonstrated that a newly formed antibiotic–anti-inflammatory multicomponent system, named norfloxacin–niflumate (NORNIF), in a salt dihydrate form, significantly improved the stability and antibiotic potency of NOR, including against the resistant microbe, as well as the solubility and in vivo anti-inflammatory effect of NIF simultaneously. In addition, preliminary in silico studies using Swiss-ADME and ProTox-3 predicted that the salt was well absorbed in the gastrointestinal tract and could be classified as toxicity class 4 (non-toxic). Full article

As the crisis of antibiotic resistance escalates, phage therapy has regained attention as an alternative strategy. Artificial intelligence (AI) technologies offer new avenues to overcome the bottlenecks inherent in traditional bacteriophage research. This review summarizes the multi-dimensional innovative applications of machine learning, deep learning, and large biological models in phage studies. In the fields of phage recognition and genomics, support vector machines (SVMs), convolutional neural networks (CNNs), and pre-trained protein language models can all achieve recognition accuracy rates of over 90%. Furthermore, tools such as DeepHost and VirSorter2 can efficiently identify phage sequences, annotate functional genes, and predict hosts at the species or strain levels. For clinical translation, AI integrates patient characteristics, bacterial phenotypes, and phage profiles to customize cocktail regimens for individualized phage therapy. Graph neural network-based models like DeepPBI-KG integrate multi-omics knowledge graphs to precisely predict phage-host interactions (PHIs), whereas agent-based simulation and defense protein predictors forecast phage resistance evolution. Additionally, generative AI can support the de novo design of functional phage genomes and mine massive unannotated virome dark matter. Nevertheless, this cross-disciplinary field faces significant constraints, including uneven and biased sequencing datasets, insufficient model interpretability, and dual-use biosafety ethical risks accompanied by unclear algorithm accountability and incomplete global supervision systems. Future research should optimize standardized multimodal databases, develop explainable AI algorithms, and establish cross-disciplinary ethical governance frameworks to facilitate closed-loop verification between computational prediction and wet-lab experiments. In conclusion, the deep integration of AI and phage biology provides revolutionary strategies to tackle multidrug-resistant infections and advances the clinical transformation of phage precision medicine. Full article

The genus Mammaliicoccus was recently reassigned from the family Staphylococcaceae. Mammaliicoccus spp. were first detected on German dairy farms, and exhibited a wide range of antimicrobial resistance genes. They are non-aureus agents frequently found in milk. Postbiotic substances (PSs) have recently emerged as a new class of functional biotics. Therefore, the objective of this study was to evaluate the in vitro effects of nisin and PS produced by autochthonous lactococci against Mammaliicoccus spp. (isolated from raw goat milk) to broaden their antimicrobial spectrum of inhibition and to indicate their potential use. Non-hemolytic, low-grade biofilm-forming (0.119 ± 0.034; 0.222 ± 0.047) strains of Mammaliicoccus vitulinus, Mv 33/3 and Mv 44, identified by sequencing, did not contain resistance genes for 15 antibiotics tested, and were susceptible to methicillin. They did not produce damaging enzymes or produced only a small amount (5–10 nmoL). In addition, they were susceptible to the bacteriocin nisin (inhibitory activities of 25,600 AU/mL and 51,200 AU/mL) and to PS produced by autochthonous lactococci (inhibitory activity of 400–800 AU/mL). Treatment of strains with postbiotic substances can minimize the risk of antibiotic resistance gene occurrence, thereby making products more stable during processing or storage. Full article

Uncomplicated urinary tract infection (uUTI) management is increasingly challenging due to antibiotic treatment failure (TF). This retrospective, observational cohort study used Optum’s de-identified Electronic Health Record dataset (January 2017–September 2022) to investigate the impact of antibiotic TF (defined as a second oral antibiotic prescription, administration of an intravenous antibiotic, or an emergency department visit/hospitalization with a new primary diagnosis of urinary tract infection <28 days post index) on clinical outcomes and healthcare resource utilization (HCRU) among women with uUTI. Eligible patients were female, aged ≥12 years, with an outpatient diagnosis of uUTI and one or more empirically prescribed oral antibiotics within ±5 days of diagnosis (index). Adjusted risk ratios (aRR) of adverse clinical outcomes were assessed ≤12 months post index (observation period), and rate ratios of all-cause and UTI-related HCRU during the index episode and observation period were observed. Of 376,004 patients, 62,873 (16.7%) experienced TF, while 313,131 (83.3%) did not. Patients with TF had significantly higher risk (aRR [95% CI]) of recurrent UTI (1.23 [1.21, 1.25]) and acute pyelonephritis (1.77 [1.70, 1.84]) (both p < 0.001) versus those without. Patients with TF had significantly greater all-cause and UTI-related HCRU versus patients without. Overall, patients with TF had significantly higher risk of adverse outcomes and greater HCRU than patients without TF. Full article

The rise of multidrug-resistant (MDR) pathogens in the pediatric population represents a significant global health challenge, compounded by a historically stagnant antibiotic pipeline for children. While several novel antibiotics have been approved for adults in recent decades, pediatric labeling is often deferred due to the complexities of developmental pharmacology and due to a certain precautionary prudence in introducing new drugs onto the market for this population. This review explores the landscape of the most recent antibiotics, including advanced cephalosporins (ceftaroline, cefiderocol, and ceftobiprole), novel beta-lactam/beta-lactamase inhibitor combinations (e.g., ceftazidime/avibactam, meropenem/vaborbactam), and long-acting lipoglycopeptides. We analyze their approval trials, pediatric-specific PK/PD profiles, and the balance between on-label use and evidence-based off-label prescriptions. Furthermore, we emphasize the role of antimicrobial stewardship through the “3 D’s” rule and the evolution of Therapeutic Drug Monitoring (TDM) from reactive safety controls to proactive, model-informed precision dosing (MIPD). Finally, we advocate for a multidisciplinary synergy between pediatricians and pharmacologists as the cornerstone for optimizing outcomes and preserving the efficacy of the future antibiotic pipeline. Full article

Antimicrobial peptides (AMPs) are increasingly regarded as next-generation antimicrobial agents because of their broad-spectrum activity, rapid killing, antibiofilm potential, immunomodulatory properties, and mechanisms of action that differ from those of many conventional antibiotics. Despite these advantages, their clinical translation remains limited by proteolytic instability, hemolysis or cytotoxicity, poor pharmacokinetics, salt and serum sensitivity, production costs, and delivery challenges. The AMP field is therefore shifting from natural peptide discovery toward integrated engineering pipelines that combine rational peptide modification, biomaterial-based delivery, high-throughput screening, and artificial intelligence (AI), particularly machine learning (ML) and deep learning approaches. Chemical and structural modifications, including D-amino acid substitution, N-glycine substitution, cyclization, lipidation, PEGylation, terminal amidation, hydrocarbon stapling, hybridization, sequence truncation, metal coordination, and biomaterial immobilization, are being used to improve stability, potency, selectivity, antibiofilm activity, and tissue localization. In parallel, AI-guided approaches, including ML, deep learning, and generative modeling, enable large-scale exploration of diverse peptide sources, including microbiomes and extinct proteomes, to entirely new sequences, while supporting optimization of potency, selectivity, stability, toxicity, and synthesizability. This focused review summarizes recent advances in AMP engineering, biomaterial-assisted delivery, and AI-guided discovery for biofilm-associated infections in the context of antimicrobial resistance. Full article

Pseudomonas aeruginosa (PA) is a formidable environmental pathogen. It causes severe and refractory bovine mastitis. The escalating threat of antimicrobial resistance requires new non-antibiotic therapies. These alternative therapies should focus on targeting host-directed responses. Sodium butyrate (SB) is a prominent short-chain fatty acid. It possesses potent immunomodulatory properties. However, its protective mechanisms against PA-induced mammary injury remain elusive. This study investigated the efficacy and underlying molecular mechanisms of SB. bMECs were pretreated with 0.5 mmol/L SB for 18 h prior to challenge with P. aeruginosa (1 × 10⁷ CFU/mL, 6 h). We evaluated its ability to alleviate PA-induced cytotoxicity in bovine mammary epithelial cells (bMECs). Flow cytometry and ELISA demonstrated the strong protective effects of SB. SB pretreatment significantly reduced PA-induced cellular apoptosis. It also suppressed the hypersecretion of pro-inflammatory cytokines, including IL-6 and TNF-α. Next, transcriptomic sequencing (RNA-seq) was performed. We identified 589 differentially expressed genes (DEGs) between the PA-challenged and SB-treated groups. These DEGs were significantly enriched in the Toll-like receptor (Tlr), Mapk, and autophagy signaling pathways. We subsequently conducted molecular validations via RT-qPCR, Western blotting, and immunofluorescence. The results revealed that SB significantly suppressed the overactivation of the TLR4/MAPK cascade. Specifically, SB significantly downregulated the expression of TLR4. It also decreased the downstream phosphorylation levels of p38, ERK, and JNK. Furthermore, PA infection induced a severe blockade of autophagic flux. This dysfunction was evidenced by the concurrent cellular accumulation of LC3-II and the autophagic substrate p62. Remarkably, SB intervention was associated with the reduction in autophagic marker accumulation, evidenced by facilitated lysosomal clearance of p62. Collectively, sodium butyrate protects bMECs against PA-induced inflammation and apoptosis. These protective effects are closely associated with the suppression of the TLR4/MAPK signaling cascade and the alleviation of autophagic marker accumulation. This highlights the potential of SB as a promising preventive strategy for the clinical management of bovine mastitis. Full article

The global spread of multidrug-resistant bacteria, alongside the rising burden of oncological diseases, poses an increasing threat to human health and public healthcare systems worldwide. Substantial efforts are underway to discover new drugs and to reposition or repurpose existing ones. Recently, nifuroxazide introduced into clinical practice in the late 1960s has attracted considerable attention due to its antitumor potential. However, its poor absorption in the intestinal tract limits its applicability as a systemic antitumor agent, a limitation that can be addressed through chemical modification. In this study, we evaluated 11 nifuroxazide analogs featuring systematic modifications to both the five-membered ring (replacement of furan with thiophene) and the six-membered aromatic ring (variation in the position and nature of substituents). MTT cytotoxicity assays performed on HCT116 and HEK293 cell lines revealed that 5-nitrofurfurylidene hydrazide of 2-pyridinecarboxylic acid and 5-nitrothien-2-yl hydrazide of 2-pyridinecarboxylic acid exhibit selective toxicity toward tumor cells while showing significantly lower toxicity to non-tumor cells, indicating potential for further investigation in more complex biological models. Antimicrobial activity testing identified 5-nitrofurfurylidene hydrazide of 3-hydroxybenzoic acid and 5-nitrofurfurylidene hydrazide of 3-pyridinecarboxylic acid as particularly potent. Full article

Due to limitations in the use of antibiotics as feed additives to promote growth, the development of safe, effective, and environmentally friendly antibiotic alternatives is a critical and urgent research priority in animal nutrition and veterinary medicine. Plants contain abundant active substances, which are important sources for developing new feed additives or discovering new active substances. Ageratina adenophora (Spreng.) R.M.King & H.Rob. (A. adenophora) is an herb native to Central America and a globally invasive species that has spread across Asia, Australia, Africa, and other continents. Studies indicated that it possesses a complex chemical composition, with over 100 constituents identified, including terpenoids, flavonoids, and phenolic acids, which exhibit diverse biological activities, including antibacterial, antioxidant, insecticidal, acaricidal, anti-inflammatory, neuroprotective, antidiabetic, antitumor, and gut health regulation effects. However, it also possesses distinct toxicity, primarily targeting organs such as the intestines, liver, and spleen, causing tissue damage by activating specific signaling pathways. This may limit its utilization as a feed additive or in medical drug development. Therefore, this review systematically summarizes the botanical characteristics, geographic distribution, phytochemical composition, biological activities, and toxicological effects of A. adenophora. We also discussed its potential application and current challenges. We hope this review can promote its development and utilization as potential feed additives or medicinal resources. Full article

Tuberculosis (TB) remains one of the most significant global public health challenges, as it represents the world’s leading infectious cause of death. The clinical efficacy of currently available anti-TB drugs is increasingly compromised due to the growing prevalence of antibiotic-resistant strains, side effects, and prolonged treatment times. This scenario highlights the urgent need to identify new anti-TB drugs with alternative mechanisms of action and improved anti-TB activity and bioavailability. In this context, natural products derived from microorganisms represent a key source of chemical diversity for drug discovery. Actinomycetes, fungi, and other environmental microbes produce a wide range of secondary metabolites with broad antimicrobial activity. These compounds can interfere with essential bacterial structures and processes, including membrane integrity, redox homeostasis, protein synthesis, and DNA replication. This review aims to evaluate new microbial natural products for their antibacterial activity, focusing on their efficacy, mechanisms of action, chemical nature, and potential clinical applications, with the aim of informing the development of new anti-TB agents. Full article

The World Health Organization (WHO) estimates that by 2050, bacterial resistance will cause 10 million deaths, of which approximately one million are associated with multidrug-resistant (MDR) microorganisms. Staphylococcus aureus is one of the bacteria with high resistance to the most widely used antibiotics that cause infections worldwide. Reports show that approximately 80% of S. aureus strains are resistant to penicillin (methicillin resistance), and that this resistance has been developing since the 1960s (WHO). On the other hand, there are new potential targets to develop new antibiotic drugs; notably, the 3-dehydroquinate dehydratase of S. aureus (SaDHQD) is relevant for this, due to the SaDHQD involved in the metabolism of the S. aureus, which is necessary in the shikimate pathway. This study proposes two compounds against SaDHQD to develop a new antibiotic drug. We performed in silico and in vitro assays for it, and in this way, this study proposes compounds that could be selected against SaDHQD, for the development of a new antibiotic drug. Full article

Background: Powassan virus (POWV) is the only tick-borne encephalitis-group flavivirus endemic to the United States (U.S.) and is an increasingly serious public health threat. Reported U.S. cases remain relatively few but have grown steadily—from fewer than two annually before 2005 to a record 60 in 2024—and neuroinvasive disease carries a 10–15% case fatality with lasting neurological sequelae in roughly half of the survivors. Examining POWV through a One Health lens, we conducted a scoping review of its ecological and zoonotic drivers, its interactions with co-circulating tick-borne pathogens, its full clinical spectrum, and its distinction from other tick-borne diseases. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidance, we searched PubMed/MEDLINE, U.S. Centers for Disease Control and Prevention (CDC) surveillance databases, state health-department publications, and vetted public-health news through early 2026. The review was conducted as an AI-integrative partnership among the authors, the Global Infectious Diseases and Epidemiology Online Network (GIDEON) database, and Claude (Anthropic), enabling a synthesis of human-curated archival records collected over six years alongside the published literature; this yielded over 200 sources, almost half unavailable through an AI search alone. Results: POWV is maintained in a sylvatic cycle involving I. scapularis ticks, small-mammal reservoirs, and incidental human spillover. Its clinical spectrum spans asymptomatic seroconversion to fatal meningoencephalitis; prodromal fever, headache, vomiting, and fatigue may progress to encephalitis, seizures, aphasia, cranial-nerve palsies, paralysis, and ataxia—the most severe neurological syndrome among U.S. tick-borne diseases. Cases cluster in the northeastern and Great Lakes states, with older males disproportionately affected, while viral evidence extends to the mid-Atlantic, southern, and western regions. POWV is distinguished by its flaviviral etiology, short (as little as 15 min) transmission window, absence of a characteristic rash, and complete antibiotic resistance. Of the 48 states surveyed, only 7 published POWV data. Conclusions: POWV is an escalating One Health threat driven by expanding vector tick ranges, land-use and climate change, and wildlife–human interface dynamics. Enhanced cross-sector surveillance integrating human, animal, and environmental monitoring, alongside improved public-health data reporting, is urgently needed. Full article

The emergence of antimicrobial resistance (AMR) has created a need for new, targeted alternatives to conventional antibiotics. Bacteriocins and other targeted antimicrobial peptides (AMPs) are emerging therapeutic approaches that have attracted attention for their potent antimicrobial properties and potential for more specific effects on microbial communities. The review describes the development of probiotics from lactic acid bacteria (LAB) to next-generation probiotics (NGPs), incorporating genomics, metagenomics, and synthetic biology to develop and engineer antimicrobial-producing microbial platforms. A comparative analysis of the bacteriocin profiles of conventional LAB and NGPs is presented, highlighting differences in diversity, specificity, and therapeutic potential. Additionally, recent advances in large-scale bacteriocin production systems, including recombinant expression and bioengineering methods, are discussed. Issues related to delivery systems, stability, host interactions, and targeted release are discussed. Most evidence comes from in vitro and animal studies, with limited clinical data on bacteriocin-producing probiotics and NGPs. There is also a significant gap in direct experimental proof of bacteriocin production by many proposed NGPs, hindering their development as targeted antimicrobials. Regulatory, scale-up, and manufacturing challenges remain major barriers to commercialization and broad therapeutic use. Target pathogen prioritization is a final step highlighted in the review that will help in therapeutic precision and improve the outcome of treatment for multidrug-resistant pathogens. Overall, LAB-derived bacteriocins have the most substantial evidence for production, characterization, and safety, while NGP-associated systems are promising but mostly preclinical and need further structural and functional validation. Moving towards precision antimicrobial therapy will depend on developing standardized activity assays, evaluating microbiome interactions, monitoring resistance, ensuring strain safety, establishing scalable manufacturing processes, and conducting comprehensive human clinical trials. Full article

Background/Objectives: Colibacillosis, caused by enteropathogenic strains of Escherichia coli (EPEC), is one of the most common infectious diseases in rabbit farms. In the past, antimicrobials were widely used to control colibacillosis, but their use in prevention is currently prohibited. Therefore, the adoption of new prevention strategies as alternatives to the use of antibiotics is very important. The aim of this study was to evaluate the antimicrobial efficacy of cinnamon essential oil (Cinnamomum zeylanicum) against EPEC strains responsible for colibacillosis in rabbits. Methods: For the experiment, 124 strains of E. coli isolated from rabbits that had died of colibacillosis in 10 industrial farms were used. Suspensions of each strain prepared according to CLSI standards with a bacterial density of 1 × 10⁸ CFU/mL were tested using 100% pure commercial cinnamon essential oil (CEO) at concentrations ranging from 0.2 to 0.8 μL/mL. Minimum inhibitory concentrations MIC₅₀ and MIC₉₀ were determined according to a protocol described previously. Results: MIC₅₀ and MIC₉₀ were 0.5 μL/mL and 0.6 μL/mL, inhibiting 64.5% and 94.3% of strains, respectively. Furthermore, strains exposed to 0.4 μL/mL were 12.9 times more likely to be inhibited than those exposed to 0.3 μL/mL (p = 0.0001). Conclusions: CEO was found to be effective against E. coli strains tested at high bacterial densities that can usually be found per gram of faeces in rabbits affected by colibacillosis. Consequently, cinnamon should be useful in preventing colibacillosis by limiting the replication of E. coli, as it is usually found in lower densities in the intestines of healthy rabbits, preventing the onset of colibacillosis and reducing the use of antibiotics in rabbit farms. Full article

Background: Stress urinary incontinence is one of the most common and debilitating complications following radical prostatectomy. Artificial urinary sphincter (AUS) implantation is the gold standard treatment for moderate to severe post-prostatectomy incontinence. Common complications include device infection, mechanical failure, component migration, urethral erosion, and urethral atrophy, which often require device removal and subsequent reimplantation. To our knowledge, erosion or migration of orthopedic osteosynthesis screws into the lower urinary tract causing new-onset urinary symptoms after AUS implantation has not previously been reported. Case Presentation: A 57-year-old man with an implanted AUS presented to the emergency department with fever, dysuria, and de novo urge incontinence. Intravenous antibiotic therapy was initiated, resulting in resolution of the fever, after which further diagnostic evaluation was performed. Cystoscopy demonstrated normal urethral coaptation and intact urethral mucosa at the cuff site. However, three orthopedic osteosynthesis screws from previous pelvic fracture fixation were identified protruding immediately below the bladder neck. The screws were removed by open surgery during ongoing empirical antimicrobial therapy. Four weeks later, the AUS was reactivated. At 8-month follow-up, the patient remained asymptomatic and maintained the same continence status as following AUS implantation. Conclusions: A detailed history of previous pelvic surgery and orthopedic fixation, together with review of available imaging, is important in candidates for AUS implantation. In patients presenting with new-onset urinary symptoms after AUS implantation, alternative etiologies should be considered, with cross-sectional imaging and cystoscopy used selectively according to the clinical presentation. Full article