Search Results (674)

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

Background/Objectives: Antimicrobial consumption (AMC) surveillance and antimicrobial stewardship (AMS) constitute effective strategies to combat the increasing antimicrobial resistance rates worldwide. Post-Soviet countries (Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, the Russian Federation, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan) implemented various elements of AMC surveillance and AMS to different extents. The limited quantity and quality of data from post-Soviet countries make it difficult to assess health system performance; therefore, this region is a blind spot in global AMR monitoring. This systematic review assesses and characterises AMC surveillance and AMS implementation in post-Soviet countries. Methods: Evidence was compiled via a search in PubMed, Google Scholar, Embase, CyberLeninka, and Scopus. The eligibility criteria included AMC surveillance- and AMS-related papers in human health within defined regions and timelines. Some literature from the official websites of international and national health organisations was included in the search. Results: As a result of the searches, screening, and critical appraisal, three peer-reviewed publications and 31 documents were selected for analysis. Eleven out of fifteen countries with updated national action plans for combating antimicrobial resistance have defined AMC surveillance and AMS as strategic objectives. All 15 examined countries submitted antimicrobial consumption data to international networks and reported the existence of approved laws and regulations on antibiotic sales. However, disparities exist in the complexity of monitoring systems and AMS implementation between high-income and low-income countries in the region. Conclusions: This review provides key insights into the existing AMC surveillance and AMS implementation in former Soviet countries. Although the approach of this review lacks quantitative comparability, it provides a comprehensive qualitative framework for national-level AMC surveillance and AMS system assessment. Full article

Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: The favorable structural features from previous series were kept while the influence of the N-Boc-piperazinyl substituent per se, as well as its ring position and its replacement by various heteroaromatic rings, was evaluated. Thus, this paper describes the preparation of the MMV030666-derived 4′-(piperazin-1-yl)benzanilides for the first time, exhibiting broad-spectrum activity not only against plasmodia but also various bacterial strains. Results: A series of insightful structure–activity relationships were determined. Furthermore, pharmacokinetic and physicochemical parameters of the new compounds were determined experimentally or in silico. Drug-likeliness according to Lipinski’s rules was calculated as well. Conclusions: A diarylthioether derivative of the lead compound was promisingly active against P. falciparum and exhibited broad-spectrum antibacterial activity against Gram-positive as well as Gram-negative bacteria. It is considered for testing against multi-resistant bacterial strains and in vivo studies. Full article

Background and objectives: ABs are widely used in dental practice in the treatment of odontogenic infections and as systemic prophylaxis in high-risk patients. However, AB overuse contributes to antimicrobial resistance (AMR), which is a major global concern. This study examined dental AB prescribing trends in Germany in 2024, focusing on the share of overall AB prescriptions, patient demographics, and commonly used agents. Methods: This retrospective cross-sectional study used data from the IQVIA Longitudinal Prescription Database (LRx), covering approximately 80% of prescriptions reimbursed by statutory health insurance funds in Germany. Patients with at least one AB prescription (ATC code: J01) issued by a dentist in 2024 were analyzed. Descriptive statistics covered age, sex, and prescribed substances. Results: In 2024, German dentists prescribed ABs to 2,325,500 patients, accounting for 13.9% of all patients in the database who received AB prescriptions. Dentists were the second-largest group of AB prescribers, surpassed only by general physicians. Amoxicillin (54.2%) was most frequently prescribed, followed by amoxicillin with clavulanic acid (24.5%) and clindamycin (21.0%). Dental patients receiving AB prescriptions were older (mean age: 49.8 years) than the general antibiotic patient population (44.7 years). Interestingly, dental AB prescriptions increased during the COVID-19 pandemic, in contrast to the sharp overall decline in AB prescriptions. Between 2015 and 2019, the proportion of dental antibiotic prescriptions showed a moderate upward tendency, followed by a marked increase during the COVID-19 pandemic and a subsequent decline. In contrast, the number of patients receiving antibiotic prescriptions from other medical disciplines decreased over the same period. One particularly notable finding was the extended use of clindamycin, a reserve AB with known side effects and resistance risks, in dentistry. Conclusions: Dentists are responsible for a significant share of AB prescriptions in Germany. The rise in dental AB prescriptions, particularly the frequent prescription of clindamycin, underscores the need for interventions such as updated clinical guidelines and awareness campaigns concerning AB-related risks and their mitigation directed at dentists. These could focus on microbial culture and sensitivity testing and patient adherence education and control for targeted AB interventions. Emphasizing preventive and alternative anti-infective treatment strategies in dentistry may also help to contain AMR. Full article

Sepsis acts as the leading cause of mortality in intensive care units, characterized by life-threatening organ dysfunction due to a dysregulated host response to infection. Vitamin D (VD) pleiotropic functions were demonstrated in different biological processes, including inflammation and immunity. VD receptor (VDR) is a member of the nuclear receptor superfamily, involved in immunoregulation and resistance to infections. Previous studies have demonstrated that VD deficiency is a potential risk factor for sepsis development, which may be regulated by VDR-related physiological processes. In this review, we present a comprehensive overview of the roles of VD and VDR in sepsis, focusing on immune modulation, anti-inflammatory and anti-infective responses, oxidative stress regulation, gut microbiome enhancement, vascular endothelial cell modulation, and antiplatelet activity. We also discuss recent advances in clinical research on VD/VDR in sepsis, considering the clinical implications and potential interventions of VD analogs and VDR ligands in treatment. Despite its challenges, VD holds potential for personalized sepsis interventions. Additionally, VD/VDR may serve as a promising bidirectional immunomodulator, capable of addressing both hyperinflammatory and immunosuppressive phases of sepsis, yet require systematic investigations into its dynamic states and functions across different sepsis phases. Ongoing study and evidence-based guidelines are crucial to maximize its therapeutic benefits and improve clinical outcomes. 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

Background/Objectives: Root canal infections represent a serious challenge to the success of endodontic treatment. The most commonly used antimicrobial irrigants, such as sodium hypochlorite (NaOCl), have certain limitations, while endodontic biofilms pose a significant microbiological complexity in the endodontic field. Silver nanoparticles (AgNPs) have emerged as a promising irrigant option in root canal treatments; however, few studies are focusing on endodontic biofilms. This work aimed to evaluate the antimicrobial and anti-adherence properties of AgNPs against clinically isolated bacteria taken directly from patients with various pulp and periapical diseases. Methods: AgNPs of two sizes were synthesized and characterized. The bactericidal and anti-adherence activities of AgNPs were evaluated through microbiological assays using experimental in vitro and ex vivo tests on oral biofilms taken from patients with symptomatic apical periodontitis (AAP) and pulp necrosis (PN). NaOCl solution was used as the gold standard. Results: The size of AgNPs was uniformly distributed (13.2 ± 0.4 and 62.6 ± 14.9 nm, respectively) with a spherical shape. Both types of nanoparticles exhibited good antimicrobial and anti-adherence activities in all microbiological assays, with a significant difference from NaOCl for in vitro and ex vivo models (p < 0.05). The inhibitory activity of AgNPs is mainly related to the type of microbiological sample and the exposure time. The antibacterial substantivity of both nanoparticle sizes was time-dependent. Conclusions: AgNPs may represent a promising antimicrobial option as an endodontic irrigant during conventional root canal treatments to prevent and control endodontic infections. 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

Since ancient times, Royal Jelly (RJ) has been known for its remarkable properties in traditional medicine, and it is still widely recommended for mental and physical well-being. RJ consists of a unique and complex mixture of multiple constituents in different concentrations, and some of its biological activities are directly associated with specific components not found elsewhere in nature, such as (E)-10-hydroxy-2-decenoic acid (10-HDA) and its precursor 10-hydroxydecanoic acid (10-HDAA), two medium-chain fatty acids. Together, 10-HAD and 10-HDAA represent the major constituents of the total lipid fraction in RJ, but despite their structural similarity, the former has been extensively investigated over the years, while the latter has been only marginally reported. This review focuses on the promising effects of 10-HDAA that have emerged in a series of recent in vitro, in vivo, and docking simulation studies. Important bioactivities were observed for 10-HDAA, tested both as an individual compound, especially for immunoregulatory, estrogenic, and anti-inflammatory activities, and in synergic combination with other molecules. Specific anti-infective effects against endemic diseases, as well as the structural modification to synthesize biocompatible and biodegradable 10-HDAA-based amphiphiles, are also reported. Full article

Chrysanthemum species represent an economically important group of flowering plants. Many species also present a medicinal interest, notably for the treatment of inflammatory pathologies. This is the case for Chrysanthemum boreale Makino, endemic to Japan and widespread in Eastern Asia. This perennial plant has long been used in folk medicine to treat inflammatory diseases and bacterial infections. An extensive review of the scientific literature pertaining to C. boreale has been performed to analyze the origin of the plant, its genetic traits, the traditional usages, and the properties of aqueous or organic plant extracts and essential oils derived from this species. Aqueous extracts and the associated flavonoids, such as acacetin and glycoside derivatives, display potent antioxidant activities. These aqueous extracts and floral waters are used mainly as cytoprotective agents. Organic extracts, in particular those made from methanol or ethanol, essentially display antioxidant and anti-inflammatory properties useful to protect organs from oxidative damage. They can be used for neuroprotection. Essential oils from C. boreale have been used as cytoprotective or antibacterial agents. The main bioactive natural products isolated from the plant include flavonoids such as acacetin and related glycosides (notably linarin), and diverse sesquiterpene lactones (SLs). Among monomeric SLs, cumambrins and borenolide are the main products of interest, with cumambrin A targeting covalently the transcription factor NF-κB to regulate proinflammatory gene expression to limit osteoclastic bone resorption. The dimeric SL handelin, which is characteristic of C. boreale, exhibits a prominent anti-inflammatory action, with a capacity to target key proteins like kinase TAK1 and chaperone Hsp70. A few other natural products isolated from the plant (tulipinolide, polyacetylenic derivatives) are discussed. Altogether, the review explores all medicinal usages of the plant and the associated phytochemical panorama, with the objective of promoting further botanical and chemical studies of this ancestral medicinal species. 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

Impetigo is a highly contagious bacterial skin infection characterized by blistering and erosions that can lead to significant discomfort and complications. The standard treatment includes topical or systemic antibiotics, but severe cases may require advanced wound management strategies. Polylactic acid (PLA)-based membranes have demonstrated effectiveness in enhancing wound healing, modulating inflammation, and reducing pain. Clinical case: We present three cases of bullous impetigo with extensive erosions, managed using PLA membranes as an adjunct to systemic antibiotics. A significant improvement was shown after 7 days of treatment of a single application, and complete resolution was achieved after 30 days. Notably, pain was resolved within 48–72 h, highlighting the analgesic and protective properties of the membrane. Conclusions: These findings suggest that PLA membranes provide a viable adjunct to antibiotic therapy in bullous impetigo, accelerating healing, reducing discomfort, and improving long-term skin outcomes. Given the increasing concern over antibiotic resistance and the limitations of standard wound care, bioresorbable synthetic membranes represent a promising alternative in dermatological wound management. Full article

Invasive bacterial gastrointestinal infections represent a substantial clinical burden worldwide, contributing to significant morbidity and, in severe cases, mortality. The causative bacterial agents of these infections include Shigella spp., enteroinvasive Escherichia coli, Salmonella spp., Campylobacter jejuni, Yersinia enterocolitica, and Listeria monocytogenes. Given the growing challenges of therapy failures and rising antibiotic resistance, there is still an unmet need to identify novel, effective, and safe compounds exhibiting antimicrobial, anti-inflammatory, and immunomodulatory activities. In the present review, we aimed to compile current data regarding three alkaloids—berberine, sanguinarine, and cheleritrin—which hold significant promise in treating bacterial invasive gastrointestinal diseases. Our review extended beyond the direct antimicrobial properties of these compounds against pathogens capable of breaching the intestinal epithelial barrier. We also presented their modulatory effects on intestinal barrier integrity and their influence on the composition and function of the resident gut microbiota, thereby highlighting their potential indirect role in attenuating pathogen invasion and disease progression. Thus, our review presents alkaloids as potential preparations that potentiate the activity of classic anti-infective drugs, as well as substances that, by affecting the microbiome and intestinal mucosa, could be used for inflammatory bowel diseases. Full article