Search Results (130)

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

The global antimicrobial resistance crisis demands innovative strategies to combat bacterial infections, including those caused by drug-sensitive pathogens that evade treatment through biofilm formation or metabolic adaptations. Here, we demonstrate that Squama Manitis extract (SME)—a traditional Chinese medicine component—exhibits broad-spectrum bactericidal activity against clinically significant pathogens, including both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) species (MIC = 31.25 mg/mL), achieving significant reduction in bacterial viability within 24 h. Through integrated multi-omics analysis combining scanning electron microscopy and RNA sequencing, we reveal SME’s unprecedented tripartite mechanism of action: (1) direct membrane disruption causing cell envelope collapse, (2) metabolic paralysis through coordinated suppression of TCA cycle and fatty acid degradation pathways, and (3) inhibition of DNA repair systems (SOS response and recombination downregulation). Despite its potent activity, SME shows low cytotoxicity toward mammalian cells (>90% viability) and can penetrate Gram-negative outer membranes. These features highlight SME’s potential to address drug-resistant infections through synthetic lethality across stress response, energy metabolism, and DNA integrity pathways. While advocating for synthetic alternatives to endangered animal products, this study establishes SME as a polypharmacological template for resistance-resilient antimicrobial design, demonstrating how traditional knowledge and modern systems biology can converge to guide sustainable anti-infective development. Full article

Anti-infectives include molecules that target microbes in the context of infection but lack antimicrobial activity under conventional growth conditions. We previously described D66, a small molecule that kills the Gram-negative pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) within cultured macrophages and murine tissues, with low host toxicity. While D66 fails to inhibit bacterial growth in standard media, the compound is bacteriostatic and disrupts the cell membrane voltage gradient without lysis under growth conditions that permeabilize the outer membrane or reduce efflux pump activity. To gain insights into specific bacterial targets of D66, we pursued two genetic approaches. Selection for resistance to D66 revealed spontaneous point mutations that mapped within the gmhB gene, which encodes a protein involved in the biosynthesis of the lipopolysaccharide core molecule. E. coli and S. Typhimurium gmhB mutants exhibited increased resistance to antibiotics, indicating a more robust barrier to entry. Conversely, S. Typhimurium transposon insertions in genes involved in outer membrane permeability or efflux pump activity reduced fitness in the presence of D66. Together, these observations underscore the significance of the bacterial cell envelope in safeguarding Gram-negative bacteria from small molecules. Full article

Streptococcus pneumoniae (S. pneumoniae) Sortase A (SrtA) anchors virulence proteins to the surface of the cell wall by recognizing and cleaving the LPXTG motif. These toxins help bacteria adhere to and colonize host cells, promote biofilm formation, and trigger host inflammatory responses. Therefore, SrtA is an ideal target for the development of new preparations for S. pneumoniae. In this study, we found that phloretin (pht) and phlorizin (phz) exhibited excellent affinities for SrtA based on virtual screening experiments. We analyzed the interactive mechanism between pht, phz, and alnusone (aln, a reported S. pneumoniae SrtA inhibitor) and SrtA based on molecular dynamics simulation experiments. The results showed that these inhibitors bound to the active pocket of SrtA, and the root mean square deviation (RMSD) and distance analyses showed that these compounds and SrtA maintained stable configuration and binding during the assay. The binding free energy analysis showed that both electrostatic forces (ele), van der Waals forces (vdw), and hydrogen bonds (Hbonds) promoted the binding between pht, phz, and SrtA; however, for the binding of aln and SrtA, the vdw force was much stronger than ele, and Hbonds were not found. The binding free energy decomposition showed that HIS141, ILE143, and PHE119 contributed more energy to promote pht and SrtA binding; ARG215, ASP188, and LEU210 contributed more energy to promote phz and SrtA binding; and HIS141, ASP209, and ARG215 contributed more energy to promote aln and SrtA binding. Finally, the transpeptidase activity of SrtA decreased significantly when treated with different concentrations of pht, phz, or aln, which inhibited S. pneumoniae biofilm formation and adhesion to A549 cells without affecting normal bacterial growth. These results suggest that pht, phtz, and aln are potential materials for the development of novel inhibitors against S. pneumoniae infection. Full article

Regulating the innate immune response against infections, particularly drug-resistant bacteria, is a key focus in anti-infection therapy. Cathelicidins, found in vertebrates, are crucial for pathogen resistance. Few studies have explored gecko cathelicidins’ anti-infection properties. Recently, five new cathelicidins (Gj-CATH1-5) were identified in Gekko japonicus. The peptide Gj-CATH5, from G. japonicus, shows promise against Pseudomonas aeruginosa through various mechanisms. This study examined Gj-CATH5’s protective effects using in vitro and in vivo models, finding that it significantly reduced bacterial load in a mouse infection model when administered before or shortly after infection. Flow cytometry and the plate counting method showed that Gj-CATH5 boosts neutrophil and macrophage activity, enhancing chemotaxis, phagocytosis, and bactericidal functions. Gj-CATH5 increases ROS production, MPO activity, and NET formation, aiding pathogen clearance. Its amphipathic α-helical structure supports broad-spectrum bactericidal activity (MBC: 4–8 μg/mL) against Gram-negative and antibiotic-resistant bacteria. Gj-CATH5 is minimally cytotoxic (<8% hemolysis at 200 μg/mL) and preserves cell viability at therapeutic levels. These results highlight Gj-CATH5’s dual role in pathogen elimination and immune modulation, offering a promising approach to combat multidrug-resistant infections while reducing inflammation. This study enhances the understanding of reptilian cathelicidins and lays the groundwork for peptide-based immune therapies against difficult bacterial infections. Full article

Background: Saudi Arabia is undertaking a comprehensive reform of its healthcare system to improve the efficiency and accessibility of public healthcare services. A key aspect of this initiative is outsourcing outpatient pharmacy services within the public health sector to retail pharmacies through an electronic prescribing platform known as Wasfaty. The National Unified Procurement Company (NUPCO) manages this platform to ensure spending efficiency and patient accessibility to essential medications. However, there has been a lack of research evaluating the adherence of the Wasfaty e-prescribing platform to established best practices for Computerized Provider Order Entry (CPOE), which are commonly used to assess the performance of various ambulatory e-prescribing systems globally. Objective: This study aimed to assess the level of adherence of Wasfaty to best practices for CPOE. Methods: This descriptive cross-sectional single-center study reviewed filled prescriptions through Wasfaty from May 2022 to December 2023. A list of 60 functional features, including but not limited to patient identification and data access, medication selection, alerts, patient education, data transmission and storage, monitoring and renewals, transparency and accountability, and feedback, was utilized to evaluate adherence. The adherence level was categorized into four groups: fully implemented, partially implemented, not implemented, and not applicable. Two pharmacy interns, a clinical pharmacist, and a researcher, reviewed the prescriptions to determine the platform’s adherence to these 60 CPOE features. Results: From May 2022 to December 2023, a total of 1965 prescriptions were filled in retail pharmacies for out-of-stock medications for 1367 patients. These prescriptions included medications for various areas, with the following distribution: gastroenterology (44.10%), cardiology (18.14%), anti-infectives (2.42%), urology (8.85%), dermatology (3.6%), hematology (0.29%), muscle relaxants (0.8%), neurology (19.17%), pulmonology (1.46%), and other categories (1.23%). Of the 60 functional characteristics a CPOE platform should include, only 19 (31.66%) were fully implemented, while 10 (16.66%) were partially implemented. Conclusions: The Wasfaty platform is deficient in several key functional features necessary for e-prescribing, which are essential for ensuring patient safety and enhancing the satisfaction of both prescribers and patients. This study underscores the importance of improving the Wasfaty platform to reduce the risk of adverse drug events. Full article

Background/Objectives: Streptococcus pneumoniae (S. pneumoniae) is a major pathogen causing severe infectious diseases, with an escalating issue of antimicrobial resistance that threatens the efficacy of existing antibiotics. Given the challenges in developing traditional antibiotics, drug repurposing strategies offer a novel approach to address the resistance crisis. This study aims to evaluate the antibacterial and anti-biofilm activities of the approved non-antibiotic anticancer drug carmofur against multidrug-resistant S. pneumoniae, and investigate the mechanism of action, and assess therapeutic potential in vivo. Methods/Results: Antimicrobial tests revealed that carmofur exhibited strong antibacterial activity against multidrug-resistant S. pneumoniae strains, with minimum inhibitory concentrations (MICs) ranging from 0.25 to 1 µg/mL. In the biofilm detection experiments, carmofur not only inhibited the formation of biofilms, but also effectively removed biofilms under high concentration conditions. Mechanistic studies showed that carmofur disrupted bacterial membrane permeability and decreased intracellular ATP levels. Molecular docking and dynamics simulation assays indicated that carmofur could stably bind to thymidylate synthase through hydrogen bonding and hydrophobic interactions, thereby exerting antibacterial effects. Meanwhile, carmofur was able to repress the expression of the thyA gene at the mRNA level. In a mouse infection model, the carmofur treatment group showed a reduction of approximately two log levels in bacterial load in lung tissue and blood, a significant decrease in the levels of inflammatory cytokines TNF-α and IL-6, and an improvement in survival rate to 60%. Conclusions: In summary, carmofur demonstrated significant antibacterial and anti-biofilm activities against multidrug-resistant S. pneumoniae and showed good anti-infective effects in vivo, suggesting its potential clinical application as a therapeutic agent against drug-resistant bacteria. Full article

Background: On-demand personalized drug production is currently not addressed with large-scale drug manufacturing. In our study, we focused primarily on identifying possible active pharmaceutical ingredients (APIs) for 3D Printing (3DP) in the current healthcare setting. Methods: We conducted a retrospective cross-sectional study in the Netherlands using three different sources; community pharmacies (n = 5), elderly care homes (n = 3), and the Erasmus MC Sophia Children’s Hospital. The primary endpoint was the percentage of prescriptions of medication manipulated before administration, thereby being a candidate for 3DP. Around a million prescriptions were analyzed in our study. Results: This study shows that around 3.0% of the prescribed drugs dispensed by Dutch community pharmacies were manipulated before administration, while around 10.5% of the prescribed drugs in the Erasmus MC Sophia Children’s Hospital were manipulated prior to administration. Conclusions: With our study, we show that the most manipulated drugs come from the groups of constipation, psychopharmaceutical, cardiovascular, and anti-infectant drugs. Successful introduction of a compounded API drug by 3DP does not only rely on the API, but it also comes with an optimal balance between technical, economic as well as societal impact factors. Our study gives direction for potential future research on the introduction of 3DP of medicine in the healthcare setting. Full article

Mosquito-borne diseases are a group of illnesses caused by pathogens transmitted by mosquitoes, and they are globally prevalent, particularly in tropical and subtropical regions. Pathogen transmission occurs during mosquito blood feeding, a process in which mosquito saliva plays a crucial role. Mosquito saliva contains a variety of biologically active proteins that facilitate blood feeding by preventing blood clotting, promoting vasodilation, and modulating the host’s immune and inflammatory responses. These effects create an environment conducive to pathogen invasion and dissemination. Specific mosquito salivary proteins (MSPs) can promote pathogen transmission through mechanisms that either regulate hosts’ anti-infective immune responses or directly enhance pathogens’ activity. Strategies targeting these MSPs have emerged as an innovative and promising approach for the control of mosquito-borne diseases. Meanwhile, the diversity of these proteins and their complex interactions with the host immune system necessitate further research to develop safer and more effective interventions. This review examines the functional diversity of MSPs and their roles in disease transmission, discusses the advantages and challenges of strategies targeting these proteins, and explores potential future directions for research in this area. Full article

In orthopedics, the use of anti-infective biomaterials is considered the most promising strategy to contrast the bacterial contamination of implant surfaces and reduce the infection rate. KSL, KSL-W, and Dadapin-1 are three antimicrobial peptides (AMPs) that possess significant antibacterial properties, making them promising candidates for producing anti-infective biomaterials not based on antibiotics. To fully assess their true potential, this study explores in detail their cytocompatibility on human osteoblast-like MG63 cells, murine fibroblastoid L929 cells, and hMSCs. To this end, the cytotoxicity of the AMPs in terms of IC₅₀ was tested over a range of concentrations of 450–0.22 µg/mL using the ATP bioluminescence assay. The tests were performed both in the presence and absence of bovine serum to assess the effects of serum components on peptide stability. IC₅₀ values obtained under the most stringent conditions were used to extrapolate the selectivity index (S.I.) toward salient bacterial species. In medium containing serum, all AMPs exhibited minimal to no cytotoxicity, with IC₅₀ values exceeding 100 µg/mL. Dadapin-1 was the peptide that exhibited the lowest cytotoxicity, KSL-W exhibited the highest stability, and KSL exhibited the highest selectivity. Overall, these findings highlight the potential of these AMPs for the future production of anti-infective materials. Full article

Skin grafting is a critical procedure for treating skin defects from burns, trauma, and surgical interventions, yet complications such as ischemia, necrosis, and infection can limit graft success. Hyperbaric Oxygen Therapy (HBOT) has emerged as a promising adjunctive treatment that enhances skin graft viability through mechanisms including enhanced oxygenation, angiogenesis, reduced inflammation, and anti-infective effects. This review synthesizes findings from clinical studies, comparative analyses, and case reports to clarify HBOT’s efficacy in improving skin graft outcomes. Methods include a comprehensive analysis of HBOT’s impact on graft take rates, healing times, and complication rates. Results indicate that HBOT significantly improves graft survival by mitigating ischemia and infection, while comparative studies show a reduction in major amputations and improved healing in complex cases, such as diabetic foot ulcers and traumatic injuries. These findings suggest that HBOT can serve as a valuable adjunct to standard grafting procedures, offering a multifaceted approach to improve graft viability, especially in high-risk cases. This review highlights HBOT’s potential for integration into wound management protocols, providing a foundation for further exploration into its efficacy and applications in reconstructive surgery. Full article

Eye infections are a global health and economic problem that affect people of both sexes at any age. Topical application of anti-infectives is widely used in the treatment of these types of infections. However, little is known about the current status and trends of the use of topical ocular anti-infectives in Spain. In the present work, we evaluated the use of this type of drug in the Spanish autonomous community of Galicia and described the variability in its consumption between Galician provinces between 2020 and 2023. In addition, the possible existence of a deviation in consumption at a seasonal level was evaluated, as well as possible changes during the study period. A descriptive, cross-sectional and retrospective study of the use of drugs belonging to the subgroups S01A (anti-infectives) and S01C (anti-inflammatory agents and anti-infectives in combination) of the Anatomic Therapeutic Chemical Classification was carried out. This work demonstrated that the most used topical ocular anti-infective in Galicia was tobramycin and that the use of these types of drugs in our region varied according to the provinces. This study also revealed that the consumption of these medications has remained stable during the period 2020–2023, with no significant seasonal differences observed. Full article

Inflammation and thrombosis are implicated in several non-communicable chronic disorders, including cardiovascular diseases, diabetes, renal and neurodegenerative disorders, skin diseases, and especially in cancer. Natural bioactives and especially phytochemicals like phenolic compounds have been proposed to reduce the inflammatory burden with several health benefits against these disorders. Vanillin is a phenolic compound found in the seeds of various species of vanilla plants. It has been known since ancient times for its aromatic and soothing properties; however, recent outcomes have outlined several other pleiotropic actions for this phenolic bioactive compound. Within this article, the potent anti-inflammatory activities of vanillin and its derivatives are thoroughly reviewed, with emphasis on their anti-cancer, anti-infective, wound-healing, and neuroprotective health-promoting properties. The mechanisms of their action(s), along with recent outcomes from in vitro and in vivo studies and clinical trials, on the benefits of these vanillin-based phenolic bioactives against each of these disorders, and especially against specific types of cancer, are also outlined. Limitations and future perspectives of their use solely as bioactive ingredients, as ingredients in several functional products—such as functional foods, supplements, nutraceuticals, or even cosmetics and drugs—and even as adjuvant therapies are also discussed. Full article

Introduction: Polymethylmethacrylate (PMMA) is the most widely used denture base material due to its favourable properties. Several studies have tested the incorporation of anti-infective agents into PMMA as a strategy to prevent biofilm growth on the denture surface. This systematic review aims to evaluate the efficacy of incorporating inorganic antimicrobial particles into denture base resins in preventing antimicrobial growth, thereby identifying the most effective agents for enhancing PMMA’s antimicrobial properties. Materials and methods: This systematic review followed the PRISMA guidelines, and the research protocol was registered in PROSPERO. The search was performed by using Medical Subject Headings and free text combined with Boolean operators in PubMed/Medline^® and in Cochrane^® and a free text combination in Web of Science^® Core Collection. Data regarding the inorganic particles studied, their antimicrobial effect, and the type of samples produced were collected and analysed. Results: After screening, a total of fifteen studies were included in this review. Most samples were disk-shaped and of varying sizes, and the most tested microbial strain was Candida albicans. Silver was the most used antimicrobial particle, followed by gold, titanium, and copper. Conclusions: Overall, incorporating inorganic particles into PMMA has produced promising antimicrobial results, depending on the concentration. Due to the high heterogeneity observed in the samples, more studies are recommended, particularly clinical trials. Full article

Background/Objectives: Bacterial resistance and virulence are challenges in treating bacterial infections, especially in Klebsiella pneumoniae. Plants of the Launaea Cass. genus are used traditionally to address a variety of diseases, including infections, but the potential bioactive compounds are unknown. Our goals were to verify the potential contribution of two major polyacetylene glycosides isolated from our previous study, (3S,6E,12E)-6,12-tetradecadiene-8,10-diyne-1-ol 3-O-β-D-glucopyranoside (1) and bidensyneoside A (syn. gymnasterkoreaside A) [(3R,8E)-3-hydroxy-8-decene-4,6-diyn-1-yl β-D-glucopyranoside] (2), to the anti-infective properties of Launaea capitata and to develop a dependable HPLC method for their quantification; Methods: On a panel of K. pneumoniae clinical isolates, the antibacterial action of 1, 2, and the methanol extract of the whole L. capitata plant were evaluated by broth microdilution assay, while their antibiofilm action was evaluated by the crystal violet assay. qRT-PCR investigated luxS, mrkA, wzm, and wbbm genes that encode biofilm formation and quorum sensing (QS). The antibacterial activity of 1 was revealed by employing mice infection. Chromatographic separation was conducted using isocratic elution on a Hypersil BDS C18 column using a photodiode array (PDA) detector; Results: Compound 1 showed antibacterial activity with MIC values of 16–128 µg/mL. It remarkably reduced strong and moderate biofilm-forming bacterial isolates from 84.21% to 42.1% compared with the extract (68.42%) and 2 (78.95%). Compound 1 also downregulated the QS genes, luxS, mrkA, wzm, and wbbm, and exhibited in vivo antibacterial action through the enhancement of the histological construction of the liver and spleen, decreased TNF-α immunoreaction, bacterial burden, and the inflammatory mediators IL-1β and IL-6. A successful HPLC-PDA approach was developed to separate the binary mixture of 1 and 2 in less than 10 min with high sensitivity, with detection limits down to 0.518 and 0.095 µg/mL for 1 and 2, respectively; Conclusions: Compound 1 exhibited remarkable antibacterial and antibiofilm properties and may contribute to the anti-infectious traditional uses of L. capitata, meriting further clinical studies and serving as a reliable quality control biomarker for the plant. Full article