Search Results (510)

Background/Objectives: Pseudomonas aeruginosa is a notorious multidrug-resistant pathogen that causes serious acute and chronic infections by employing quorum sensing (QS)-regulated virulence, biofilm formation, and host-damaging inflammation. To overcome the yield limitation of two previously identified marine secondary metabolites with dual QS inhibitory and PPAR-γ agonistic activities, we further screened marine-derived natural products for more abundant candidates with similar anti-virulence and anti-inflammatory properties. Methods: In this study, isoflavones were evaluated for anti-QS and PPAR-γ transactivation activities using reporter gene assays, and for antibacterial, anti-virulence, and anti-inflammatory effects via broth microdilution, biofilm, G. mellonella infection, and ELISA cytokine assays. Results: Daidzein and genistein were selected for their optimal anti-QS and PPAR-γ activation activities. They inhibited a key QS regulator and suppressed pyocyanin production and biofilm formation in P. aeruginosa without affecting bacterial growth, indicating minimal selective pressure for resistance. In addition, daidzein and genistein were found to synergistically sensitize the wild-type P. aeruginosa strain to gentamicin, carbenicillin, tobramycin, ampicillin, and polymyxin B, and synergistically or partially synergistically sensitize a multidrug-resistant strain to gentamicin, tobramycin, and ampicillin. Moreover, a Galleria mellonella infection model confirmed that daidzein and genistein significantly enhance the efficacy of gentamicin against P. aeruginosa infection in vivo. Furthermore, in host macrophages, daidzein and genistein significantly inhibited LPS-induced production of NO, IL-6, and IL-1β when combined with an RXR agonist, implying a protective effect on host tissues through PPAR-γ activation. Conclusions: These findings demonstrate that daidzein and genistein serve as effective adjuncts to conventional antibiotics, exerting multifaceted actions against P. aeruginosa infection. Full article

The global emergence of multidrug-resistant fungal pathogens, including Candida auris, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Pneumocystis jirovecii, poses a growing threat to public health, particularly among immunocompromised individuals. The limited number of available antifungal drug classes and the rapid evolution of resistance mechanisms, including target-site mutations, efflux pump activation, biofilm formation, metabolic adaptation, and stress-response signaling, have substantially reduced treatment efficacy. This review provides a comprehensive overview of current antifungal therapies, their limitations, and emerging molecular targets for next-generation antifungal drug discovery. We highlight promising targets involved in fungal cell wall biosynthesis, membrane integrity, mitochondrial metabolism, virulence regulation, and host–pathogen interactions, emphasizing their interconnected roles within adaptive resistance networks. Attention is given to small-molecule isothiazolone-based inhibitors, including phosphoglucomutase-targeting compounds, as novel candidates capable of disrupting multiple fungal survival pathways. We further discuss advances in combination therapies, anti-virulence approaches, nanotechnology-based delivery systems, and artificial intelligence-driven drug discovery pipelines that integrate multi-omics data, structural modeling, molecular docking, and virtual screening to accelerate therapeutic development. These advances support a transition from conventional single-target strategies toward systems-level, precision-guided antifungal therapies, providing a framework for overcoming multidrug resistance and improving clinical outcomes in invasive fungal infections. Full article

Rhizogenic Agrobacterium (Rhizobium) spp. are causative agents of hairy root disease (HRD), a major threat to hydroponic crop production worldwide. The use of specific bacteriophages is considered a prospective approach to control the development of HRD in greenhouses. A combination of diverse bacteriophages is a key step to overcome potential phage resistance in the pathogen. In this study, a novel lytic bacteriophage, named Miki, was identified and characterized for its antibacterial potential against a rhizogenic Agrobacterium sp. strain circulating in greenhouses in Central Russia. High-throughput sequencing revealed a 63,458 bp double-stranded DNA genome (G + C content 53%), with 117 predicted coding sequences, considering Miki as a lytic candidate phage for plant protection. Electron microscopy of phage Miki shows a morphology unusual for Agrobacterium phages, and phylogenetic analysis attributes it as a representative of a previously undescribed taxon at least at the genus level. The paper presents a detailed analysis of the genome and structural proteome of phage Miki, including in silico predictions and modeling of receptor-binding proteins, including central and proximal fibers resembling the adsorption apparatus of Escherichia phage T5. Full article

Background: Here, we report the isolation and identification of a Paenibacillus polymyxa strain from the citizen science project, Swab and Send. P. polymyxa is well known for its production of polymyxin E (colistin), and polymyxin B. Polymyxins are ranked in the highest-priority critically important antimicrobial classification by the WHO and are of particular importance for treating Gram-negative multi-drug-resistant pathogens. Due to their clinical use, most of the literature focusses on these polymyxin variants, and there is sparse genetic research on other polymyxin variants. Methods: The Paenibacillus polymyxa 1G strain was isolated and tested for antimicrobial activity using a combination of on-agar and liquid-based inhibition assays to detect antimicrobial activity against Escherichia coli. The isolate was also tested for activity in liquid media against a panel of isolates showing various resistances to test if our strain could overcome current clinically important resistance mechanisms. Our isolate was whole-genome-sequenced, and bioinformatics was carried out on the resulting sequence to analyse the relevant biosynthetic gene cluster. The cell-free supernatant from the P. polymyxa 1G isolate was also analysed using mass spectrometry to confirm the production of the polymyxin. Results: P. polymyxa 1G was active on agar and resulted in antimicrobial activity, with a 99% reduction in area under the curve when tested in liquid media against E. coli. P. polymyxa 1G did not inhibit the growth of E. coli containing mcr-1 or mcr-4 colistin-resistance genes. Using whole genome sequencing, we are able to describe the biosynthetic gene cluster of the putative polymyxin A, compare the pmxA, pmxB, and pmxE genes to five other polymyxin genes that encode known polymyxin variants, and provide mass spectrometry data that supports the production of polymyxin A₁ (1157 m/z) and A₂ (1143 m/z). Conclusions: Here, we report the isolation and identification of a P. polymyxa strain producing a polymyxin A-like compound that was discovered through the citizen science project, Swab and Send. We add to the genetic and mass spectrometry data for polymyxin A, and demonstrate that this putative polymyxin A, produced naturally by our strain, is unable to overcome the current clinically relevant resistance mechanisms to colistin. Full article

Background: Antimicrobial resistance (AMR) is among the most pressing challenges in modern infectious medicine, driving progressive failure of standard antibacterial therapy and rising mortality from infections caused by multidrug-resistant (MDR) pathogens. Antibiotic potentiation through adjuvant compounds capable of restoring the activity of existing drugs represents a promising strategy to overcome resistance without developing fundamentally new antibacterial molecules. This study aimed to evaluate the antibiotic-potentiating activity of a dextrin/polyvinyl alcohol/iodine complex (D/PVA/I-1), developed at the Scientific Center for Anti-Infectious Drugs JSC (Almaty, Kazakhstan), against clinically relevant MDR reference strains. Methods: Nine reference strains, Staphylococcus aureus (ATCC 33591, BAA-39), Escherichia coli (ATCC BAA-196, BAA-2523), Klebsiella pneumoniae (ATCC BAA-2524, 700603), Acinetobacter baumannii (ATCC BAA-1790), Streptococcus pneumoniae (ATCC BAA-660), and Haemophilus influenzae (ATCC 33930), and two clinical isolates, P. aeruginosa SCAID PHRX1-2019 and E. coli SCAID WND1-2021, were tested. Antibiotic-potentiating activity was assessed by checkerboard assay with calculation of the fractional inhibitory concentration index (FICI); bactericidal kinetics were evaluated by time-kill analysis. The effect of D/PVA/I-1 on cytoplasmic membrane permeability was investigated using a crystal violet uptake assay. Results: Of 45 D/PVA/I-1–antibiotic combinations tested across nine antibiotics, synergy (FICI ≤ 0.5) was demonstrated in 44.4% of cases, partial synergy in 48.9%, and additive effects in 6.7%; no antagonistic interactions were detected. The most pronounced potentiating effect occurred against Gram-positive pathogens, particularly MRSA strains (66.7% synergistic combinations). Time-kill analysis confirmed suppression of the regrowth phenotype characteristic of MDR strains under monotherapy and restoration of bactericidal activity against antibiotics to which strains exhibited intrinsic resistance. D/PVA/I-1 induced a dose- and time-dependent increase in membrane permeability in both Gram-positive and Gram-negative organisms. Conclusions: D/PVA/I-1 is an effective broad-spectrum antibiotic potentiator and represents a promising basis for combination therapy regimens against MDR infections. Full article

Helicobacter pylori is one of the most common bacterial pathogens in humans and the primary etiological agent of chronic gastritis, peptic ulcer disease, and gastric cancer. Its ability to establish persistent gastric colonization relies on multiple virulence factors, including adhesins, urease, cytotoxins, motility, outer membrane vesicles, and biofilm formation, which collectively promote bacterial survival, chronic inflammation, and treatment failure. The increasing prevalence of antibiotic-resistant H. pylori strains has intensified the search for therapeutic strategies targeting both bacterial viability and virulence. Berberine (BBR), a natural isoquinoline alkaloid, has emerged as a promising candidate because of its antibacterial, anti-inflammatory, and antioxidant properties. Increasing evidence derived from native berberine, its derivatives, and berberine-based formulations indicates multifaceted anti-H. pylori activity, including direct antibacterial effects, inhibition of virulence determinants, and modulation of host inflammatory responses. This review summarizes current knowledge on the epidemiology and pathogenic mechanisms of H. pylori and provides a comprehensive overview of the available evidence regarding the anti-H. pylori pharmacological profile of BBR-based compounds. Particular attention is given to their effects on bacterial adhesion, motility, urease activity, efflux pump function, biofilm formation, and host inflammatory signaling pathways. The review also discusses findings from preclinical and clinical studies supporting BBR-based strategies as adjuncts to conventional eradication therapies. In addition, recent advances in nanotechnology-based drug delivery systems designed to overcome the poor oral bioavailability of BBR and improve its therapeutic efficacy against H. pylori are highlighted. 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

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

Bovine mastitis, caused by both contagious and environmental pathogens, represents a major infectious disease burden in the global dairy industry. Antibiotics remain the primary treatment option, but their effectiveness is limited by the blood–milk barrier, drug residues, and the growing threat of multidrug-resistant bacteria. Among the various alternatives, phage therapy has drawn particular attention due to its specificity, ability to disrupt biofilms, low impact on commensal flora, and self-replication at infection sites. In this review, we summarize recent advances in the isolation of lytic phages targeting major mastitis-causing pathogens, their bactericidal mechanisms, and their performance in vitro and in vivo. We also discuss key obstacles to clinical translation including formulation stability, narrow host range, and safety concerns. Moreover, the potential strategies to overcome these issues are explored. This review provides a useful reference for research on phage therapy against bovine mastitis. Full article

The rapid emergence and dissemination of antimicrobial resistance (AMR) among bacterial pathogens, particularly the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), represents one of the most pressing global public health challenges, contributing to increased morbidity, mortality, and healthcare costs. The limited development of new antibiotic classes over the past two decades has intensified the search for structurally novel antimicrobial agents and adjuvants capable of overcoming multidrug resistance. Natural products continue to serve as an invaluable source of anti-infective drug leads owing to their remarkable structural diversity and broad spectrum of biological activities. Mangrove ecosystems, located at the interface of terrestrial and marine environments, harbor highly diverse microbial communities, including fungi that have evolved under extreme environmental conditions and produce a wide range of unique secondary metabolites. Beyond their ecological significance, mangrove-associated fungi have emerged as prolific producers of bioactive compounds with promising antibacterial activity against multidrug-resistant pathogens. This review comprehensively summarizes recent advances (2018–2026) in the discovery of antibacterial metabolites from mangrove-associated fungi active against ESKAPE pathogens, which discusses their structural diversity, reported antimicrobial activities, and emerging strategies for accelerating natural product discovery, including genome mining, metabolomics, OSMAC, adaptive laboratory evolution, and artificial intelligence-assisted approaches. A total of 139 chemically distinct metabolites (Compounds 1–139) isolated from mangrove-associated fungi are critically reviewed, highlighting their potential as promising leads for the development of next-generation antimicrobial agents against ESKAPE pathogens. Full article

Nanomedicine-based liposomal delivery systems are gaining increasing attention as advanced therapeutic platforms for managing ocular infections associated with antimicrobial resistance (AMR) and biofilm formation. The primary objective of this review is to critically evaluate the potential of liposomal drug delivery systems for improving the treatment of antimicrobial-resistant and biofilm-associated ocular infections by integrating current knowledge on antimicrobial resistance mechanisms, biofilm-targeted therapeutic strategies, and advances in liposomal formulations, while also identifying the major limitations, translational challenges, and knowledge gaps in this rapidly evolving field. Traditional ocular antimicrobial treatments are frequently limited by poor drug penetration, short precorneal residence time, low bioavailability, systemic side effects, and inadequate activity against resistant microorganisms and biofilm-embedded pathogens. This review provides a comprehensive overview of different liposomal systems, including conventional, cationic, polyethylene glycol (PEG)-modified, deformable, and stimulus-responsive liposomes, and discusses their advantages in ophthalmic drug delivery, such as enhanced corneal permeation, prolonged drug retention, controlled release, improved biocompatibility, and reduced ocular toxicity. The review further examines the mechanisms through which liposomes help overcome AMR, including improved epithelial transport, membrane disruption, intracellular drug delivery, efflux pump evasion, and enhanced antimicrobial efficacy. In addition, liposomal approaches targeting ocular biofilms are explored, focusing on improved biofilm penetration and the delivery of anti-biofilm agents such as antibiotics, enzymes, quorum-sensing inhibitors, and antimicrobial peptides. Current evidence from in vitro and in vivo ocular infection models is summarized together with disease-specific applications in keratitis, endophthalmitis, and contact lens-related infections. The article also compares liposomes with other ocular nanocarriers and addresses important considerations related to safety, stability, sterilization, large-scale production, and regulatory translation. In addition to highlighting recent advances, this review critically discusses the current limitations of liposomal formulations, the major barriers to clinical translation, and the key knowledge gaps that should be addressed to facilitate the future development and successful clinical application of these systems. Finally, emerging directions including ligand-targeted and stimulus-responsive liposomes, AI-driven formulation development, personalized nanotherapy, and gene therapy combinations are discussed as promising future strategies for combating resistant ocular infections. Full article

The increasing serotypic diversity and multidrug resistance of Riemerella anatipestifer pose a serious threat to the poultry industry, necessitating novel antimicrobial agents. Although phage-derived endolysins offer rapid and specific bactericidal activity with low resistance potential, their efficacy against this Gram-negative pathogen is severely constrained by the outer membrane barrier, driving the need for strategies to enhance endolysin penetration. In this study, the native endolysin NA of phages vB_RanS_CRP2 was verified to lack antibacterial activity. To overcome this barrier, we constructed three chimeric proteins—ALC001, ALC005, and ALC007—by fusing a receptor-binding protein, a cell-penetrating peptide, or a polycationic nonapeptide, respectively. All three chimeras exhibited dose-dependent antibacterial activity, with ALC005 demonstrating the best performance. ALC005 achieved a lytic rate of 72.2% against the tested Riemerella anatipestifer strains, remained stable at 0–40 °C and pH 6–9, and was shown by transmission electron microscopy to exert its bactericidal effect by disrupting the bacterial cell envelope and inducing cell lysis. Collectively, cell-penetrating peptide fusion is a reliable and effective strategy to potentiate endolysin activity against Riemerella anatipestifer. Full article

The rise of antimicrobial resistance and the persistence of difficult-to-treat infections have stimulated interest in new strategies to overcome these problems. Among these strategies, dendrimers, which are highly branched monodisperse macromolecules, have emerged as innovative antimicrobial and anti-infective platforms. Dendrimers can act as intrinsic antimicrobial agents through multivalent interactions or membrane disruption or serve as nanocarriers for antibiotics, antiviral agents, antibiofilm compounds, gas-releasing active molecules, or photosensitizers. This review analyzes dendrimer-based anti-infective systems for which in vivo or clinical evaluation has been reported. The literature covers diverse platforms, including PAMAM, poly(L-lysine), peptide, carbosilane, phosphorhydrazone, polyglycerol, polyester, and other dendritic architectures. The available evidence includes infected animal models, pharmacokinetic and biodistribution studies, local tolerance studies, and clinical trials. PAMAM systems are the most extensively explored preclinically, whereas poly(L-lysine) dendrimer astodrimer/SPL7013 remains the most clinically advanced example. Overall, dendrimers provide a chemically tunable and biologically versatile approach to anti-infective research, but the current evidence remains heterogeneous. Direct comparison across studies is limited by differences in dendrimer scaffold, generation, surface chemistry, formulation, pathogen, infection model, administration route, dosing regimen, and biological endpoint. Future development will require better-defined in vivo models, more systematic safety and biodistribution studies, clearer structure–activity relationships, and stronger links between in vitro activity and clinically relevant efficacy. Full article

The ecological adaptations of insect pests, such as multi-niche colonization and physiological resistance to conventional chemicals, pose severe challenges to the sustainable production of sweet potato (Ipomoea batatas). The tobacco whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae), and the sweet potato weevil, Cylas formicarius (Coleoptera: Brentidae), form a highly destructive, spatially separated pest complex. In this study, we evaluated the dual-niche pathogenicity of a Beauveria bassiana (Hypocreales: Cordycipitaceae) isolate, BbCF-2, generated via spaceflight mutagenesis, against C. formicarius and B. tabaci under controlled laboratory conditions. The mutated strain exhibited enhanced colony expansion and a high sporulation capacity (2.72 × 10⁸ conidia/mL). Bioassays revealed that BbCF-2 possesses significantly increased virulence compared to the wild-type strain, capable of overcoming the distinct physiological and physical barriers of both targeted pests. Against the highly sclerotized subterranean C. formicarius adults, BbCF-2 achieved 92.68% mortality at 15 days post-inoculation at 1 × 10⁸ conidia/mL, with an LC50 of 8.452 × 10³ conidia/mL and an LT50 of 6.305 days. Concurrently, against the canopy-dwelling B. tabaci, the isolate demonstrated rapid lethal mycosis with an LT50 of 6.718 days, effectively reducing the adult vector population prior to their typical dispersal timeframe. These results demonstrate that the spaceflight-mutated BbCF-2 strain exhibits broad pathogenicity. By simultaneously targeting both foliar and soil-dwelling pests, this single-agent biological control strategy shows potential for integrated pest management, pending greenhouse and field evaluation. Full article

Blackleg disease, caused by Leptosphaeria spp. fungi, is a major contributor to significant global yield losses in Brassica napus. Thus, selecting resistant plants using molecular markers linked to resistance loci is a common mitigation strategy. The latter, however, faces a challenge as pathogen virulence can overcome host resistance. This necessitates the identification of superior resistant genotypes through the use of numerous novel molecular markers and simplified detection methods to accelerate breeding programs. Based on our previous work, this study evaluated and verified molecular markers linked to blackleg disease resistance. A crucial finding is the identification of polymorphisms within SilicoDArT-type marker sequences that directly confer resistance. We also provide primer sequences for conventional PCR-based detection of SNP-type and SilicoDArT-type markers and a modified PCR protocol to enhance SNP detection efficiency. These validated markers and optimized PCR conditions are expected to significantly aid plant breeders in developing new, more resistant rapeseed varieties. Full article