Search Results (2,991)

Invasive fungal diseases (IFDs) are a global health threat, especially among immunocompromised populations, due to their high mortality rates and the increasing prevalence of antifungal resistance. In recognition of this threat, the World Health Organization (WHO) has designated Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans as critical-priority fungal pathogens. During host infection, host-derived reactive oxygen species (ROS) function as potent antimicrobial molecules, whereas fungal-derived ROS act as intracellular signaling mediators regulating oxidative stress adaptation, metabolism, virulence, and antifungal tolerance. Although oxidative stress responses have been extensively investigated in individual fungal pathogens, a comprehensive comparative analysis of oxidative stress signaling across these critical fungal pathogens remains limited. This review systematically compares oxidative stress sensing and signaling networks in the four WHO critical-priority fungal pathogens and classifies oxidative stress-associated pathways into conserved, and species-specific regulatory mechanisms. Conserved pathways, including HOG-MAPK, calcineurin, cAMP-PKA, cell wall integrity, and thioredoxin-dependent signaling, are discussed alongside pathogen-specific adaptations that promote biofilm formation, capsule and melanin production, polarized growth, morphogenesis, immune evasion, and antifungal resistance. By integrating conserved and divergent oxidative stress signaling mechanisms, this review provides a comparative framework that advances our understanding of fungal pathogenesis and highlights potential targets for the development of broad-spectrum and species-specific antifungal therapies. Full article

Implant-associated infections (IAIs) persist as a critical complication in biomaterial transplantation, driven by rapid microbial colonization, biofilm encapsulation, and escalating antibiotic resistance. Conventional antibiotic-based treatments and passive antimicrobial coatings often fail to achieve long-term infection control due to limited biofilm penetration, localized cytotoxicity, and active agent depletion. To overcome these limitations, piezoelectric nanocomposite coatings utilize a dynamic, stimulus-responsive framework that converts physiological mechanical forces or external ultrasound into localized electrical signals. These surface-bound electric fields systematically mitigate bacterial adhesion, eradicate mature biofilms via targeted reactive oxygen species (ROS) generation, disrupt microbial metabolic pathways, and favorably modulate the peri-implant immune microenvironment while supporting host tissue repair. This review evaluates the material design principles and classifications of inorganic, organic, and hybrid piezoelectric nanocoatings. We detail their multifaceted antibacterial mechanisms and trace their therapeutic potential in orthopedic and dental implants, as well as wound management. Lastly, we analyze current engineering bottlenecks to chart a clear trajectory for their clinical translation. Full article

Antimicrobial resistance (AMR) is usually addressed through surveillance, prescribing policy, stewardship programs, infection prevention, and drug development. Less attention is given to an earlier educational question: how future doctors first learn to connect microorganisms, antibiotics, and resistance. In some preclinical medical curricula, microbiology provides essential knowledge of microbial structure, virulence, antimicrobial mechanisms, laboratory diagnosis, and resistance pathways, but opportunities to use this knowledge for antimicrobial reasoning may be limited. Students may therefore recall resistance mechanisms yet remain less prepared to interpret culture and susceptibility reports, consider local resistance patterns, or explain when therapy should be escalated, narrowed, optimized, or discontinued. This Perspective argues that AMR education should begin before students prescribe. Preclinical microbiology should preserve its scientific foundation while more deliberately linking microbial mechanisms to clinical scenarios, stewardship principles, microbiology report interpretation, and assessment design. Implementation should be adapted to local standards, supported by faculty development, and evaluated prospectively. Full article

Staphylococcus aureus (S. aureus) is a prominent foodborne pathogen that poses a continuous threat to global public health and food safety due to its possession of a variety of toxins and its multidrug resistance. Medium-chain fatty acids (MCFAs), notably lauric acid (LA), exhibit strong antimicrobial properties, but their application is heavily constrained by poor water solubility. In this study, optimized LA emulsions stabilized by chitosan (CS) and polyvinyl alcohol (PVA) were evaluated for their antibacterial activity and detailed mode of action against S. aureus ATCC 6538. The antibacterial activities were evaluated by the maximum inhibition zone, with the 20 CS-PVA/DLTA-LA formulation exhibiting stable dispersion and potent antibacterial activity at 1%. The underlying antibacterial mechanisms against S. aureus were specifically focused on cell membranes and peptidoglycan. Therein, the binding of emulsion droplets to the anionic bacterial surface was driven by electrostatic attraction. Membrane degradation was also observed with membrane dysfunctions involving membrane depolarization, increased permeability, and fluidity reduction triggered by their subsequent insertion into the lipid bilayer, which may cause cell dysmetabolism, disintegration, and eventual cell death. Overall, these findings substantiate that LA emulsions disrupt S. aureus by operating potentially multi-targeted effects involving cell membrane disruption and peptidoglycan interference, offering a promising alternative approach warranting further investigation for foodborne pathogen control. Full article

Nontoxigenic Bacteroides fragilis (NTBF) is defined by the absence of the bft gene and corresponding B. fragilis toxin production; however, nontoxigenic status alone does not establish uniform safety or probiotic function. This review critically evaluates strain-level biological characteristics, safety, mechanisms, metabolites, and disease-model evidence. Selected strains and defined strain-derived preparations, including ZY-312, HCK-B3, NCTC 9343-derived polysaccharide A, and ZY-312-derived zwitterionic capsular polysaccharide preparation TP2, have shown immunomodulatory, barrier-associated, and microbial-community-modulating activities, predominantly in vitro and in animal models. Direct causal evidence is limited to specific strain–preparation–host–model combinations, whereas many changes in cytokines, tight-junction-associated proteins, microbial composition, and organic-acid profiles remain functional or associative. Protective effects have been reported in preclinical models of inflammatory bowel disease, necrotizing enterocolitis, antibiotic-associated diarrhea, Clostridioides difficile infection, and enterotoxigenic B. fragilis (ETBF)-associated tumorigenesis. However, findings are highly dependent on the strain, preparation, dose, administration timing, host, and model. Safety remains incompletely resolved because the absence of B. fragilis toxin (BFT) does not exclude opportunistic or systemic infection, antimicrobial-resistance mobility, bacterial translocation, permeability changes, or adverse effects during long-term administration. Metabolic effects may also be beneficial or adverse depending on the strain, host dietary and genetic background, and experimental context. Human evidence is primarily observational, and robust intervention trials are lacking. Accordingly, NTBF should be regarded as a heterogeneous group of strain-specific live-biotherapeutic candidates requiring rigorous strain-specific manufacturing, potency, dose, antimicrobial-susceptibility, and safety evaluation. Full article

Background/Objectives: Antimicrobial resistance is a critical threat to global public health. Eugenol is a bioactive compound with broad-spectrum antimicrobial activity that has attracted increasing interest as a naturally derived antimicrobial agent with potential complementary applications to conventional antibiotics, but its clinical application is severely limited by its high volatility, low water solubility and thermo-oxidative instability. The main objective of this study was to develop eugenol-loaded microparticles using a ternary biopolymer matrix, to characterise their main physicochemical properties, and to evaluate their in vitro antimicrobial efficacy against clinically relevant bacterial reference strains. Methods: The microparticles were formulated from an emulsion of maltodextrin, gum arabic and soy lecithin, and encapsulated using a spray-drying technique. Product recovery, particle morphology assessed by scanning electron microscopy (SEM), particle size distribution determined by laser diffraction, and encapsulation efficiency quantified by GC-FID were analysed. Subsequently, antimicrobial activity was evaluated by comparing the microparticles with free eugenol using agar well diffusion and broth microdilution assays to determine the minimum inhibitory concentration (MIC) against eight bacterial strains. Results: The spray-drying process achieved a product recovery of 61.88% and an encapsulation efficiency of 52.45%. The resulting microparticles exhibited a smooth, spherical morphology with diameters of less than 20 µm. In microbiological assays, microencapsulation significantly reduced MIC values by 4- to 16-fold compared with free eugenol for susceptible strains. The formulation exhibited potent activity against most of the Gram-positive and Gram-negative pathogens tested, except for Pseudomonas aeruginosa, which remained resistant to both formulations. Conclusions: The encapsulation of eugenol in this optimised biopolymer matrix substantially improved its antimicrobial efficacy against the tested bacterial strains. These findings highlight the potential of spray-dried eugenol microparticles as a promising antimicrobial formulation and provide a basis for their further development for topical applications. Further studies are warranted to evaluate their pharmaceutical performance and antimicrobial mechanisms. Full article

Background: Staphylococcus aureus causes bloodstream and skin infections in humans. The prevalence of multidrug-resistant S. aureus strains means new antibiotics are needed. A novel antimicrobial drug named SK-03-92, a synthetic aromatic organic stilbenoid compound, kills S. aureus cells within 30 min, but an increase in both biofilm formation and persister cells occurs. SK-03-92 treatment downregulates transcription of the biofilm regulating protein regulator (brpR) gene and biofilm regulating protein sensor (brpS) gene in S. aureus. BrpR/BrpS system may be a LytTR regulatory system tied to biofilm formation, creation of persister cells, and late-stage competence in S. aureus. The aim of this study was to determine what biofilm, late-stage competence, and persister-associated genes were regulated in a brpR mutant compared to wild-type strains. Methods: In this study, involvement of BrpR in regulating other genes was assessed by comparing transcriptional changes in a brpR mutant strain to the S. aureus parent strain via RNA sequencing (RNA-Seq). Bioinformatic analysis was then performed on the RNA-Seq data to assess what biochemical pathways might be involved. Results: From these analyses, 440 genes were identified that had significant differences in transcript abundance when comparing the brpR mutant to wild-type strains. Quantitative reverse transcription polymerase chain reaction analysis confirmed bacA, icd, metE, and pdhA transcript levels were lower, whereas alr and mraY were higher in the brpR mutant versus wild-type strain. Furthermore, an enzymatic assay targeting NADH production from the pyruvate dehydrogenase complex showed lower levels in the mutant compared to wild-type strain. Conclusions: Overall, the study demonstrated several biosynthetic pathways tied to biofilm formation and late-stage competency may be regulated by BrpR and some potential leads for the mechanism of action of the SK-03-92 drug were uncovered. Full article

Azithromycin is widely used in dentistry as a systemic antibiotic, particularly for odontogenic infections and as an alternative in patients with β-lactam hypersensitivity. Beyond its antimicrobial activity, azithromycin possesses unique pharmacokinetic, anti-inflammatory, immunomodulatory, and anti-biofilm properties. Together with growing concerns regarding antimicrobial resistance and antibiotic stewardship, these characteristics have stimulated interest in local drug-delivery strategies that may reduce systemic antibiotic exposure while maintaining therapeutic efficacy. This narrative review evaluates the rationale, potential clinical applications, and current evidence supporting local azithromycin delivery in dentistry. The available literature on azithromycin pharmacology, systemic dental use, immunomodulatory mechanisms, biofilm-related effects, local drug-delivery systems, safety, and regulatory considerations was critically reviewed. Current evidence suggests that locally delivered azithromycin may achieve high drug concentrations at the target site, enhance anti-biofilm activity, modulate local inflammation, and minimize systemic exposure. Potential applications include periodontitis, peri-implant diseases, persistent endodontic infections, oral surgery, and regenerative procedures such as bone augmentation and maxillary sinus floor elevation. Emerging delivery platforms, such as hydrogels, thermoresponsive gels, nanoparticles, and chitosan-based systems, further support the feasibility of this approach. Experimental findings also indicate that azithromycin may inhibit osteoclast activity, suggesting additional benefits for bone preservation and regenerative healing. Despite these promising findings, current evidence remains limited and is derived mainly from preclinical studies and small clinical investigations. Further translational research and well-designed randomized controlled trials are needed to establish the safety, efficacy, and optimal clinical role of locally delivered azithromycin in evidence-based dental practice. Full article

Background/Objectives: Antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics in response to the escalating global threat of antimicrobial resistance (AMR), owing to their potent antimicrobial activity and low propensity for resistance development. However, their clinical application remains limited by poor selectivity and undesirable toxicity toward mammalian cells. Methods: In this study, the naturally occurring frog-derived AMP Dermaseptin-A4 (A4) was selected as a template for rational design. Guided by the principle that optimising the balance between peptide hydrophobicity and cationicity could improve bacterial membrane targeting while reducing interactions with mammalian membranes, three analogues were designed through the targeted modulation of these physicochemical properties. Results: Among the designed analogues, A4-3 exhibited the best overall biological profile. A4-3 maintained a stable α-helical conformation in membrane-mimicking environments and displayed potent antimicrobial activity against tested Gram-positive and Gram-negative bacteria while exhibiting lower haemolytic and cytotoxic effects than the parent peptide. As a result, A4-3 showed improved selectivity, achieving a selectivity index of up to 34.5. A4-3 rapidly eradicated bacterial cells through a membrane-targeting mechanism, leading to membrane disruption and the loss of cellular integrity, and exhibited a low propensity for resistance development following prolonged exposure. A4-3 also retained its antimicrobial activity under physiologically relevant conditions. Conclusions: Collectively, these findings demonstrate that achieving an optimal balance between peptide hydrophobicity and cationicity is an effective strategy for enhancing antimicrobial selectivity without compromising antibacterial activity, highlighting A4-3 as a promising lead candidate for the development of novel antimicrobial therapeutics against drug-resistant bacterial infections. Full article

The COVID-19 pandemic led to a dramatic increase in healthcare-associated infections and antimicrobial resistance, particularly in intensive care units (ICUs). The aim of this study was to provide a comprehensive genomic characterisation of all clinically significant opportunistic pathogens (OPs) isolated from patients and the hospital environment in COVID-19 ICUs, and to use these data to reconstruct transmission pathways, identify reservoirs, and assess the molecular mechanisms of antimicrobial resistance and virulence. Whole-genome sequencing (WGS) was performed on 175 isolates isolated from patients and the hospital environment (including personal protective equipment, PPE) between 2021 and 2023. The species collection included nine OP species. Bioinformatic analysis included multilocus sequence typing, core genome single-nucleotide polymorphism analysis, phylogenetic reconstruction, and in silico detection of resistance and virulence genes and plasmid replicons. High-risk multidrug-resistant (MDR) clones were identified among Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, and Staphylococcus aureus. Core genome SNP analysis confirmed direct transmission of K. pneumoniae between patients and healthcare worker medical gloves. PPE was identified as a major reservoir, accounting for 68.4% of environmental isolates. The study demonstrates the power of WGS for high-resolution epidemiological surveillance, confirms the critical role of contaminated PPE in nosocomial transmission, and highlights the dominance of internationally spreading MDR clones in COVID-19 ICUs. Full article

Urinary tract infections (UTIs) caused by Klebsiella pneumoniae are an increasing challenge in pediatric practice due to the combined effects of biofilm formation, multidrug resistance (MDR), and limited therapeutic options for children. Biofilm development promotes bacterial persistence by impairing antibiotic penetration, enabling metabolic adaptation, promoting persister-cell formation, facilitating horizontal gene transfer (HGT), and inducing stress-induced mutagenesis, thereby reducing the effectiveness of conventional antimicrobial therapy. These mechanisms are further compounded by pediatric-specific challenges, including age-dependent pharmacokinetic variability, congenital urinary tract abnormalities, device-associated infections, and the limited availability of validated diagnostic tools for biofilm-associated infections. This narrative review integrates current knowledge of the molecular mechanisms underlying biofilm-mediated antimicrobial resistance with the unique diagnostic, pharmacological, and therapeutic challenges encountered in pediatric patients with K. pneumoniae UTIs. Emerging therapeutic strategies, such as optimized antibiotic combination therapy, bacteriophages, biofilm matrix-degrading enzymes, quorum-sensing inhibitors (QSIs), antimicrobial peptides (AMPs), and microbiome-directed approaches are critically evaluated with particular emphasis on their potential applicability in children. Although several anti-biofilm strategies have demonstrated encouraging results in experimental models, robust pediatric clinical evidence remains scarce. Current international guidelines continue to rely primarily on planktonic antimicrobial susceptibility testing without addressing biofilm-specific therapeutic considerations. In the absence of validated biofilm diagnostics, catheter stewardship and dosing optimization remain the most defensible clinical interventions available today. Broader translation of anti-biofilm strategies into pediatric practice will require dedicated pharmacokinetic studies, standardized biofilm diagnostics, and prospective clinical trials. Full article

Antimicrobial resistance is a major global health challenge that has created an urgent need for new antibacterial agents capable of overcoming emerging resistance mechanisms. Among nitrogen-containing heterocycles, pyrrolidine has been widely investigated in medicinal chemistry due to its structural versatility, favourable physicochemical properties, and ability to enhance interactions with biological targets. This review provides a comprehensive and critical overview of pyrrolidine-based compounds investigated for antibacterial applications. Relevant studies describing clinically approved antibiotics, natural products, synthetic derivatives, hybrid molecules, and antibacterial adjuvants containing a pyrrolidine scaffold were collected, classified, and critically evaluated, with particular emphasis on structural features, antibacterial activity, and structure–activity relationships. The reviewed evidence demonstrates that the pyrrolidine moiety is present in several antibacterial drug classes, including carbapenems, cephalosporins, fluoroquinolones, lincosamides, streptogramins, and tetracyclines, where it contributes to improved target affinity, antibacterial potency, and pharmacokinetic behaviour. Numerous recently reported pyrrolidine derivatives have shown promising activity against clinically relevant, multidrug-resistant bacterial pathogens. The pyrrolidine scaffold is valuable for the design of next-generation antibacterial agents and resistance-modifying compounds, though further in vivo studies and pharmacological evaluation are required to support their clinical development. Full article

Photocatalytic antibacterial coatings have emerged as a promising antibiotic-free strategy for combating healthcare-associated infections, biofilm formation, marine biofouling, and environmental microbial contamination. Unlike conventional antimicrobial approaches, photocatalytic systems continuously generate reactive oxygen species (ROS) under light irradiation, enabling broad-spectrum antimicrobial activity while minimizing the risk of antimicrobial resistance. This review systematically summarizes the fundamental mechanisms underlying photocatalytic antibacterial activity, including photogenerated charge-carrier dynamics, ROS generation pathways, and microbial inactivation processes. We further highlight recent advances in photocatalyst design, spanning conventional semiconductor photocatalysts, heterojunction engineering, cocatalyst modification, and two-dimensional material-assisted strategies for enhanced photocatalytic performance. Crucially, particular emphasis is placed on coating architectures and interfacial regulation, including encompassing fabrication methodologies, coating–substrate adhesion, internal heterointerface design, and coating–microorganism interactions, which dictate long-term durability and antibacterial efficacy. Finally, we explore the diverse applications of these coatings in medical devices, environmental remediation, and marine antifouling, while identifying current bottlenecks and future research trajectories toward developing durable, highly efficient, and clinically translatable antimicrobial surface technologies. Full article

Antimicrobial resistance (AMR) remains an ongoing and critical concern with substantial consequences for global public health. Although recent attention has focused on managing Gram-negative infections, Gram-positive pathogens contribute comparably to morbidity and mortality. The increasing prevalence of multidrug-resistant (MDR) Gram-positive infections has led to the widespread use of vancomycin and other next-line agents including linezolid, daptomycin, ceftaroline and dalbavancin. However, emerging resistance to these agents is increasingly reported, further limiting the available therapeutic options for Gram-positive infections. To this end, there is an urgent need for effective strategies to overcome resistance, including combination therapy, optimization of pharmacokinetic and pharmacodynamic parameters, and improved source control to reduce infection burden. Additionally, resistance surveillance, antimicrobial stewardship and the development of novel antimicrobials are warranted to address the rising threat of resistant Gram-positive infections. This review aims to provide an overview of resistance mechanisms in major Gram-positive pathogens and discuss existing and emerging approaches to overcome resistance to agents beyond vancomycin, incorporating recent evidence on combination therapies and providing a practical treatment algorithm. Full article

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide. The growing prevalence of antimicrobial resistance among Enterobacterales, particularly to β-lactam antibiotics, contributes to treatment failures and prolonged hospital stays. This single-center descriptive surveillance study aimed to evaluate the distribution of Enterobacterales recovered from culture-positive urine samples in the Provincial Specialist Hospital in Włocławek, Poland, and to determine the prevalence of β-lactam resistance phenotypes among these isolates. Urine culture results collected between January and December 2025 from all hospital wards and the outpatient urology clinic were retrospectively analyzed in this study, with 1090 positive urine cultures included. For a subset of 85 isolates, microbiological findings were additionally linked with patients’ clinical characteristics. Bacteria of the genus Escherichia were the most frequently isolated (53.8%), followed by Klebsiella (22.9%) and Proteus (14.2%), with the remaining Enterobacterales genera recovered at frequencies ranging from 0.6% to 4.5%. Most isolates presented no detectable β-lactam resistance phenotype; however, resistance mediated by β-lactamase production was observed in some of them. Phenotypic ESBL and AmpC producers accounted for 25.3% and 0.6% of isolates, respectively, whereas phenotypic carbapenemase-producing strains were detected less frequently, with MBL and KPC producers representing 1.4% and 0.3% of isolates, respectively. No clear associations were identified between patient characteristics and the occurrence of specific bacterial isolates or resistance mechanisms, which may be explained by the relatively homogeneous study population, the majority of whom were ≥70 years old (66/85; 77.6%) and had a similar burden of comorbidities. In conclusion, the current level of β-lactam resistance phenotypes among urinary Enterobacterales in our setting can be considered moderate. Nevertheless, continuous surveillance of local urine-derived bacteria and their antimicrobial resistance profiles remains essential for optimizing effective control strategies. Full article