Search Results (472)

Cancer and infectious diseases are major causes of global morbidity and mortality stressing the need to find novel drugs with promising dual anticancer and antimicrobial efficacy. Gold complexes have been studied for the past years due to their anticancer properties, with a few of them displaying antimicrobial properties, which support their pharmacological interest. Within this scope, we investigated six gold bisdithiolate complexes [Au (bdt)₂]⁻ (1), [Au (dcbdt)₂]⁻ (2), [Au (3-cbdt)₂]⁻ (3), [Au (4-cbdt)₂]⁻ (4), [Au (pdt)₂]⁻ (5) and [Au (dcdmp)₂]⁻ (6), and) against the ovarian cancer cell lines A2780 and A2780cisR, the Gram-positive bacteria Staphylococcus aureus Newman, the Gram-negative bacteria Escherichia coli ATCC25922 and Burkholderia contaminans IST408, and the pathogenic yeasts Candida glabrata CBS138 and Candida albicans SC5134. Complexes 2 and 6, with ligands containing aromatic pyrazine or phenyl rings, substituted with two cyanonitrile groups, showed after 24 h of incubation high anticancer activities against A2780 ovarian cancer cells (IC₅₀~5 µM), being also able to overcome cisplatin resistance in A2780cisR cells. Both complexes induced the formation of ROS, activated caspase-3/7, and induced necrosis (LDH release) in a dose-dependent way, in a greater extent in the case of 6. Among the bacterial and fungal strains tested, only complex 6 presented antimicrobial activity against S. aureus Newman, indicating that this complex is a potential novel anticancer and antibacterial agent. These results delve into the structure-activity relationship of the complexes, considering molecular alterations such as replacing a phenyl group for a pyrazine group, and the inclusion of one or two cyanonitrile appendage groups, and their effects on biological activity. Overall, both complexes were found to be promising leads for the development of future anticancer drugs against low sensitive or cisplatin resistant tumors. Full article

The rise of multidrug-resistant Pseudomonas aeruginosa underscores the need for novel therapeutic targets beyond conventional peptidoglycan biosynthesis. Some bacterial strains bypass MurA inhibition by fosfomycin via a cell wall salvage pathway. This study targeted P. aeruginosa AmgK (PaAmgK) and MurU (PaMurU) to identify inhibitors that could complement fosfomycin therapy. A malachite-green-based dual-enzyme assay enabled efficient activity measurements and high-throughput chemical screening. Screening 232 compounds identified Congo red and CTAB as potent PaMurU inhibitors. A targeted mass spectrometric analysis confirmed the selective inhibition of PaMurU relative to that of PaAmgK. Molecular docking simulations indicate that Congo red preferentially interacts with PaMurU through electrostatic contacts, primarily involving the residues Arg28 and Arg202. The binding of Congo red to PaMurU was corroborated further using SUPR-differential scanning fluorimetry (SUPR-DSF), which revealed ligand-induced thermal destabilization. Ongoing X-ray crystallographic studies, in conjunction with site-directed mutagenesis and enzyme kinetic analyses, aim to elucidate the binding mode at an atomic resolution. Full article

Functional glycomimetics is suited to study the parameters of carbohydrate recognition that forms the basis of glycobiology. It is particularly attractive when a glycoligand allows for the investigation of two different states, such as varying distance between multiple glycoligands. Here, a xylopyranoside was employed as a scaffold for the presentation of two mannoside units which are ligands of the bacterial lectin FimH. The chair conformation of the central xyloside can be switched between a ⁴C₁ and a ¹C₄ conformation whereby the two conjugated mannoside ligands are flipped from a di-equatorial into a di-axial position. Concomitantly, the distance between the two glycoligands changes and, as a consequence, so does the biological activity of the respective bivalent glycocluster, as shown in adhesion–inhibition assays with live bacteria. Molecular modeling was employed to correlate the inter-ligand distance with the structure of the formed glycocluster–FimH complex. Our study suggests that conformational switches can be employed and further advanced as smart molecular tools to study structural boundary conditions of carbohydrate recognition in a bottom-up approach. Full article

In the present research, metal–organic framework-5 (MOF-5) was synthesized and loaded with zerumbone (ZER@MOF-5), followed by the evaluation of its anticancer, antibacterial, antifungal, DNA-binding, and free radical scavenging potentials. The synthesized nanoparticles were characterized using X-ray diffraction, ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, and scanning electron microscopy. The in vitro anticancer activity of ZER@MOF-5 was studied in a human breast cancer cell line (MCF-7) using the CCK-8 assay. The interaction of ZER@MOF-5 with pBR322 plasmid DNA was assessed by gel electrophoresis. The antimicrobial effect of ZER@MOF-5 was examined in gram-positive and gram-negative bacterial strains and yeast strains using the microdilution method. The free radical scavenging activity was assessed using the DPPH assay. Cytotoxicity assay revealed a notable enhancement in the anticancer activity of zerumbone upon its encapsulation into MOF-5. The IC₅₀ value for ZER@MOF-5 was found to be 57.33 µg/mL, which was lower than that of free zerumbone (IC₅₀: 89.58 µg/mL). The results of the DNA-binding experiment indicate that ZER@MOF-5 can bind to target DNA and cause a conformational change in DNA. The results of the antibacterial activity experiment showed that the antibacterial ability of ZER@MOF-5 was limited compared to free zerumbone. The results of the DPPH assay demonstrated that the antioxidant activity of free zerumbone was higher than that of ZER@MOF-5. MOFs encapsulate compounds within their porous crystalline structure, which leads to prolonged circulation time compared to single ligands. Although the unique structure of MOFs may limit their antibacterial and antioxidant activity in the short term, it may increase therapeutic efficacy in the long term. However, to fully understand the long-term antibacterial and antioxidant effects of the ZER@MOF-5, further comprehensive in vitro and in vivo experiments are necessary. This finding indicates that the MOF-5 could potentially be an impressive carrier for the oral administration of zerumbone. Full article

Antioxidants derived from plant extracts have attracted considerable attention due to their potential in mitigating oxidative damage through free radical scavenging mechanisms. Although 700 species have been used for centuries in Georgian traditional medicine, the chemical composition and antioxidant and antibacterial properties of Caucasian endemic medicinal plants remain largely unknown. In this study, the antioxidant and antibacterial activities of leaf and root extracts of Caucasian endemic medicinal plants Sempervivum transcaucasicum Muirhead and Paeonia daurica subsp. mlokosewitschii (Lomakin) D. Y. Hong were investigated. The highest antioxidant activity and phenolic and flavonoid content were revealed in Paeonia daurica leaf extract. The analysis of the content of water-soluble antioxidants revealed the highest content of reduced glutathione and ascorbate in Paeonia daurica leaves. Moreover, the antibacterial activity of leaf and root extracts against Escherichia coli ATCC 25922 strain was investigated, and minimal inhibitory concentration (MIC) values were determined. While the antibacterial activity against E. coli ATCC 25922 was not revealed for the Sempervivum transcaucasicum leaf extract, antibacterial properties were detected for the root extract (MIC 5 mg/mL). Collectively, the highest antibacterial activity was revealed for Paeonia daurica leaf and root extracts (MIC 2 mg/mL and 3 mg/mL, respectively). From a molecular perspective, molecular docking simulations were performed using HDOCK software, with reduced glutathione and ascorbic acid as ligands, in order to analyse their potential binding affinity to the OmpX protein. Inhibiting this protein would likely disrupt bacterial function and produce an antibacterial effect. Our results provide a possible mechanism for the antibacterial activity of Paeonia daurica subsp. mlokosewitschii. Overall, the results of the study demonstrate the potential of Caucasian endemic medicinal plants as natural antioxidants and antimicrobial agents. Full article

The increasing diversity and escalating drug resistance of bacterial pathogens have significantly compromised the efficacy of conventional antimicrobial agents, creating formidable challenges in modern infection control. These developments underscore the critical need for innovative therapeutic strategies to address the persistent global health burden posed by microbial resistance. While metal-based compounds have been extensively studied for their anticancer properties in clinical applications, their potential in antimicrobial contexts remains relatively underexplored. This review systematically elaborates on the structure-activity relationship of metal complexes, with a focus on the unique characteristics of metal drugs that differ from organic small molecules. These drugs can overcome drug resistance through various mechanisms (such as generation of reactive oxygen species and penetration of biological membranes). Understanding these mechanisms provides a crucial basis for guiding ligand design and the development of delivery systems. Full article

The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a critical threat to global health, creating an urgent need for novel antimicrobial agents. In this study, we evaluated a small library of natural and semisynthetic phytocannabinoids against a broad panel of MDR Gram-positive bacterial strains, evidencing very good activity in the low µM range. We provide evidence of the antibacterial activity of the two separated enantiomers of cannabidiol, offering novel insights into the stereochemical aspects of their bioactivity. To investigate the possible molecular targets and clarify the mechanism of action, we employed Inverse Virtual Screening (IVS), a computational approach optimized for predicting potential protein–ligand interactions, on three selected MDR bacterial species. Interestingly, key targets belonging to important bacterial metabolic pathways and defense mechanisms were retrieved, and the results were used to rationalize the observed biological activities. To the best of our knowledge, this study marks the first application of IVS to microorganisms, offering a novel strategy for identifying bacterial protein targets. The results pave the way for future experimental validation, structure-based drug design, and the development of novel antibacterial agents. Full article

A nitro-derivative of fenamic acid (4′–nitro–fenamic acid) was synthesized and used as ligand for the synthesis of four Co(II) complexes in the absence or presence of the N,N′-donors 2,2′–bipyridylamine, 1,10–phenanthroline and 2,9–dimethyl–1,10–phenanthroline. The characterization of the resultant complexes was performed with diverse techniques (elemental analysis, molar conductivity measurements, IR and UV-vis spectroscopy, single-crystal X-ray crystallography). The biological evaluation of the compounds encompassed (i) antioxidant activity via hydrogen peroxide (H₂O₂) reduction and free radical scavenging; (ii) antimicrobial screening against two Gram-positive and two Gram-negative bacterial strains; (iii) interactions with calf-thymus (CT) DNA; (iv) cleavage of supercoiled pBR322 plasmid DNA (pDNA), in the dark or under UVA/UVB/visible light irradiation; and (v) binding affinity towards bovine and human serum albumins. The antioxidant activity of the compounds against 2,2′–azinobis–(3–ethylbenzothiazoline–6–sulfonic acid) radicals and H₂O₂ is significant, especially in the case of H₂O₂. The complexes exhibit adequate antimicrobial activity against the strains tested. The complexes interact with CT DNA through intercalation with binding constants reaching a magnitude of 10⁶ M⁻¹. The compounds have a significantly enhanced pDNA-cleavage ability under irradiation, showing promising potential as photodynamic therapeutic agents. All compounds can bind tightly and reversibly to both albumins tested. Full article

Metal oxide nanoparticles (NPs) are known to have biological activity against various microorganisms; thus, they have been widely used as microbicidal agents, and their use poses potential solutions to problems such as biofouling. This study focuses on the surface modification of TiO₂ and ZrO₂ nanoparticles with lactic acid (LA) and stearic acid (SA) to enhance their antibacterial activity (AA). The surface modification of TiO₂ and ZrO₂ nanoparticles was performed using continuous frequency ultrasound. Sonication was performed at different reaction times. Characterization of the modified nanoparticles by TGA, DSC, XRD, FTIR, and XPS techniques demonstrated the presence of the organic ligand on the surface of the nanoparticles. The surface modification results in a reduction in the crystal size of the nanoparticles. Regarding the antibacterial properties of modified TiO₂ and ZrO₂ nanoparticles, their minimum bactericidal concentration (MBC) against Gram-negative and Gram-positive bacteria of the bacterial strains Escherichia coli and Staphylococcus aureus was evaluated. The results obtained from the AA of the modified and unmodified nanoparticles demonstrated greater efficacy of the modified nanoparticles, in the particular case of TiO₂ and TiO₂-LA, evaluated at concentrations of 200, 500, 800, 1100, and 1400 ppm, TiO₂-LA nanoparticles showed better results at most of the concentrations studied and a bacterial inhibition percentage of 99.0% was achieved at a concentration of 500 ppm against the Escherichia coli bacteria, while TiO₂ NPs only reached 55.0%, this shows that ligands with more than one functional group play an important role in improving AA. Full article

The Campylobacter genus includes many pathogenic species, with Campylobacter hepaticus primarily implicated in spotty liver disease in poultry. Chemotaxis is one of the well-established mechanisms of pathogenesis of Campylobacter. The chemoreceptor Tlp3, previously studied in C. jejuni, mediates responses to diverse ligands. Differences between the ligand-binding pockets of Tlp3s in C. hepaticus and C. jejuni may influence ligand specificity and niche adaptation. Here, we report a method for production of the ligand-binding domain of C. hepaticus Tlp3 (Ch Tlp3-LBD) in Escherichia coli inclusion bodies that yields crystallisable protein. Size-exclusion chromatography analysis showed Ch Tlp3-LBD is a monomer in solution. Ch Tlp3-LBD was crystallised using PEG 6000 and LiCl as the precipitants. The crystal lattice symmetry was P222₁, with unit cell geometry of a = 82.0, b = 137.7, c = 56.1 Å, and α = β = γ = 90°. X-ray diffraction data have been acquired to 1.6 Å resolution using synchrotron radiation. Estimation of the Matthews coefficient (V_M = 2.8 ų Da⁻¹) and the outcome of molecular replacement suggested the asymmetric unit is composed of two protein molecules. This work lays the foundation for studies towards understanding the structural basis of ligand recognition by C. hepaticus Tlp3 and its role in pathogenesis. Full article

The extensive research and studies conducted over the past decade have greatly improved our comprehension of the pathogenesis and risk factors associated with Spondyloarthritis (SpA). In addition, they have contributed to the advancement of novel therapeutic approaches. Although genetics still represents the primary risk factor for SpA, increasing evidence presented in this review suggests that environmental factors—such as air pollution, smoking, gut microbiota (GM), infections, and diet—also contribute to its pathogenesis. In detail, environmental particulate matters (PMs), which include ligands for the aryl hydrocarbon receptor—a cytosolic transcription factor responsive to toxic substances—facilitate the differentiation of T Helper 17 (Th17) cells, potentially exacerbating the autoinflammatory processes associated with SpA. Furthermore, smoking influences both the cellular and humoral aspects of the immune response, resulting in leukocytosis, impaired leukocyte functionality, and a decrease in various cytokines and soluble receptors, including interleukin (IL) 15, IL-1 receptor antagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R), as well as the vascular endothelial growth factor (VEGF) receptor. Studies have indicated that patients with SpA exhibit an increased prevalence of antibodies directed against a conserved epitope shared by the human leukocyte antigen B27 (HLA-B27)- and Klebsiella nitrogenase, in comparison to HLA-B27-positive controls. Additionally, current evidence regarding the GM suggests the presence of a gut–joint–skin axis, wherein the disruption of the mucosal barrier by specific bacterial species may enhance permeability to the gut-associated lymphoid tissue (GALT), resulting in localized inflammation mediated by Th1 and Th17 cells, as well as IL-17A. Finally, this review discusses the role of diet in shaping the microbial composition and its contribution to the pathogenesis of SpA. A comprehensive understanding of the mechanisms by which environmental factors influence the pathogenesis and progression of the disease could facilitate the development of novel personalized therapies targeting both external and internal environmental exposures, such as the gut microbial ecosystem. Full article

The integration of chirality into nanomaterials holds significant potential for improving molecular recognition and biomedical technologies. In this work, we fabricated novel chiral horned gold nanostructures (HNS) by controlling the concentration of chiral ligands L-/D-cysteine (Cys). The unique three-dimensional morphology with horns-rotational arrangement enables synergistic optimization of chiral optical responses and surface-enhanced Raman scattering (SERS) performance. The proposed chiral HNSs can be used to recognize amino acid enantiomers, in which homochiral amino acid has distinct affinities to the chiral HNSs of homogeneous handedness. The 4-mercaptobenzoic acid (4-MPBA)-modified D-HNS demonstrates significantly enhanced targeting affinity for D-amino acids in the Escherichia coli (E. coli) cell wall, enabling successful amplification of SERS signals and advancing bacterial detection methodologies. By demonstrating the rotation-selective interaction between chiral HNSs and circularly polarized light (CPL), D-HNS exhibits excellent photothermal conversion efficiency under right-handed circularly polarized light (RCP) irradiation. This enables the synergistic combination of targeted physical disruption and photothermal sterilization, which leads to efficient eradication of E. coli. The D-HNS hydrogel composite system further expands the practical application of photothermal sterilization. Altogether, chiral HNSs have achieved SERS detection of bacteria and efficient polarization photothermal sterilization, which helps further develop applications based on chiral nanomaterials. Full article

Pathogenic bacteria of the genus Leptospira are the etiological agents of leptospirosis, a disease that affects humans and animals worldwide. Despite the increasing number of studies, the mechanisms of leptospiral pathogenesis remain poorly comprehended. In this study, we report various interactions of the LigA7’-13’ and LigB1’-7’ domains with host components. The LigA7’-13’ and LigB1’-7’ were cloned into the pET28a vector, and the recombinant proteins were expressed in E. coli C43 (DE3) and E. coli BL21 (DE3), respectively. Both recombinant protein domains were expressed in soluble form and purified using nickel-chelating chromatography. The rLigA7’-13’ and rLigB1’-7’ domains exhibited binding to several types of integrins, with most interactions occurring in a dose-dependent and saturable manner, consistent with the characteristics of typical receptor-ligand interactions. The recombinant domain LigA7’-13’ demonstrated affinity for the glycosaminoglycans (GAGs) chondroitin-4-sulfate, chondroitin sulfate, heparin, chondroitin sulfate B, and heparan sulfate, while no binding was detected for LigB1’-7’ with these molecules. Both rLigA7’-13’ and rLigB1’-7’ interacted with components of the terminal complement pathway and were capable of recruiting C9 from normal human serum (NHS). These interactions may inhibit the formation of polyC9, ultimately preventing the assembly of the membrane attack complex (MAC). Collectively, our data expand the repertoire of host components that interact with rLigA7’-13’ and rLigB1’-7’, opening new avenues for understanding leptospiral immune evasion and broadening the roles of these domains in bacterial virulence. Full article

Background/Objectives: Nucleoside precursors and derivatives play pivotal roles in the development of antimicrobial and antiviral therapeutics. The 2022 global outbreak of monkeypox (Mpox) across more than 100 nonendemic countries underscores the urgent need for novel antiviral agents. This study aimed to synthesize and evaluate a series of 5′-O-(palmitoyl) derivatives (compounds 2–6), incorporating various aliphatic and aromatic acyl groups, for their potential antimicrobial activities. Methods: The structures of the synthesized derivatives were confirmed through physicochemical, elemental, and spectroscopic techniques. In vitro antibacterial efficacy was assessed, including minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determinations for the most active compounds (4 and 5). The antifungal activity was evaluated based on mycelial growth inhibition. Density functional theory (DFT) calculations were employed to investigate the electronic and structural properties, including the global reactivity, frontier molecular orbital (FMO), natural bond orbital (NBO), and molecular electrostatic potential (MEP). Molecular docking studies were conducted against the monkeypox virus and the Marburg virus. The top-performing compounds (3, 5, and 6) were further evaluated via 200 ns molecular dynamics (MD) simulations. ADMET predictions were performed to assess drug-likeness and pharmacokinetic properties. Results: Compounds 4 and 5 demonstrated remarkable antibacterial activity compared with the precursor molecule, while most derivatives inhibited fungal mycelial growth by up to 79%. Structure-activity relationship (SAR) analysis highlighted the enhanced antibacterial/antifungal efficacy with CH₃(CH₂)₁₀CO– and CH₃(CH₂)₁₂CO–acyl chains. In silico docking revealed that compounds 3, 5, and 6 had higher binding affinities than the other derivatives. MD simulations confirmed the stability of the protein-ligand complexes. ADMET analyses revealed favorable drug-like profiles for all the lead compounds. Conclusions: The synthesized compounds 3, 5, and 6 exhibit promising antimicrobial and antiviral activities. Supported by both in vitro assays and comprehensive in silico analyses, these derivatives have emerged as potential candidates for the development of novel therapeutics against bacterial, fungal, and viral infections, including monkeypox and Marburg viruses. Full article

Bacterial chemoreceptors sense extracellular stimuli and drive bacteria toward a beneficial environment or away from harm. Their ligand-binding domains (LBDs) are highly diverse in terms of sequence and structure, and their ligands cover various chemical molecules that could serve as nitrogen, carbon, and energy sources. The mechanism of how this diverse range of LBDs senses different ligands is essential to signal transduction. Previously, we reported that the chemoreceptor MCP2201 from Comamonas testosteroni CNB-1 sensed citrate and L-malate, altered the ligand-free monomer–dimer equilibrium of LBD to citrate-bound monomer (with limited monomer) and L-malate-bound dimer, and triggered positive and negative chemotactic responses. Here, we present our findings, showing that D-malate binds to MCP2201, induces LBD dimerization, and triggers the chemorepellent response exactly as L-malate did. A single site mutation, T105A, can alter the D-malate-bound LBD dimer into a monomer–dimer equilibrium and switch the negative chemotactic response to D-malate to a positive one. Differences in attractant-bound LBD oligomerization, such as citrate-bound wildtype LBD monomer and D-malate-bound T105A dimer, indicated that LBD oligomerization is a consequence of signal transduction instead of a trigger. Our study expands our knowledge of chemoreceptor-sensing ligands and provides insight into the evolution of bacterial chemoreceptors. Full article