Search Results (39)

Background: Salmonella infections pose a serious threat to both animal and human health worldwide. Notably, there is an increasing trend in the resistance of Salmonella to fluoroquinolones, the first-line drugs for clinical treatment. Methods: Utilizing Salmonella Typhimurium CICC 10420 as the test strain, ciprofloxacin was used for in vitro induction to develop the drug-resistant strain H1. Changes in the minimum inhibitory concentrations (MICs) of various antimicrobial agents were determined using the broth microdilution method. Transcriptomic and metabolomic analyses were conducted to investigate alterations in gene and metabolite expression. A combined drug susceptibility test was performed to evaluate the potential of exogenous metabolites to restore antibiotic susceptibility. Results: The MICs of strain H1 for ofloxacin and enrofloxacin increased by 128- and 256-fold, respectively, and the strain also exhibited resistance to ceftriaxone, ampicillin, and tetracycline. A single-point mutation of Glu469Asp in the GyrB was detected in strain H1. Integrated multi-omics analysis showed significant differences in gene and metabolite expression across multiple pathways, including two-component systems, ABC transporters, pentose phosphate pathway, purine metabolism, glyoxylate and dicarboxylate metabolism, amino sugar and nucleotide sugar metabolism, pantothenate and coenzyme A biosynthesis, pyrimidine metabolism, arginine and proline biosynthesis, and glutathione metabolism. Notably, the addition of exogenous glutamine, in combination with tetracycline, significantly reduced the resistance of strain H1 to tetracycline. Conclusion: Ciprofloxacin-induced Salmonella resistance involves both target site mutations and extensive reprogramming of the metabolic network. Exogenous metabolite supplementation presents a promising strategy for reversing resistance and enhancing antibiotic efficacy. Full article

Helicobacter pylori is a gastric pathogen implicated in peptic ulcer disease and gastric cancer. The increasing prevalence of antibiotic-resistant strains underscores the urgent need for alternative therapeutic strategies. In this study, we investigated the chemical composition and antibacterial activity of an aqueous extract from Caulerpa lentillifera (sea grape), a farm-cultivated edible green seaweed collected from Krabi Province, Thailand. Ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) revealed that the extract was enriched in bioactive nucleosides and phenolic compounds. In vitro assays demonstrated dose-dependent inhibition of H. pylori growth following exposure to sea grape extract. Furthermore, untargeted intracellular metabolomic profiling of H. pylori cells treated with the extract uncovered significant perturbations in central carbon and nitrogen metabolism, including pathways associated with the tricarboxylic acid (TCA) cycle, one-carbon metabolism, and alanine, aspartate, and glutamate metabolism. Pyrimidine biosynthesis was selectively upregulated, indicating a potential stress-induced shift toward nucleotide salvage and DNA repair. Of particular note, succinate levels were markedly reduced despite accumulation of other TCA intermediates, suggesting disruption of electron transport-linked respiration. These findings suggest that bioactive metabolites from C. lentillifera impair essential metabolic processes in H. pylori, highlighting its potential as a natural source of antimicrobial agents targeting bacterial physiology. Full article

To manage the developing resistance of Alternaria spp. [the causal fungi of ginseng Alternaria leaf and stem blight (GALSB)] to QoIs fungicides, the toxicity and biochemical activity of pyrimidine nucleoside antibiotics (PNA) against Alternaria spp., cross-resistance between PNA and eight other fungicides currently used to control GALSB disease, and the efficacy of PNA for controlling GALSB in vitro and in vivo were investigated. The distributions of EC₅₀ values of PNA against the mycelial growth (115 isolates) and conidia germination (89 isolates) of A. alternata were unimodal, with mean EC₅₀ values of 10.192 ± 4.961 μg/mL and 0.828 ± 0.101 μg/mL, respectively. There were no significant correlations between the sensitivity of A. alternata to PNA and eight other fungicides (p < 0.05). PNA caused morphological changes in A. alternata mycelia and germ tubes, increased cell membrane permeability, and reduced intracellular DNA and protein levels. On detached ginseng leaves, 300 μg/mL PNA achieved mean protective and curative effects of 87.93% and 94.77% against A. alternata 7 days post-inoculation, outperforming that of 300 μg/mL kresoxim-methyl. Field trial results showed that PNA (180 g a.i./hm²) achieved mean efficacies of 85.63%, 84.07%, and 72.55% at three sites 7, 15, and 30 days after the last spray, which were 5.28–37.74% higher than those of control fungicides pyraclostrobin, azoxystrobin, and kresoxim-methyl at corresponding time points. Overall, our findings indicate that PNA are effective agents for the management of Alternaria spp. resistance to QoIs fungicides. Full article

The degradation of sulfadiazine (4-amino-N-pyrimidin-2yl-benzenesulfonamide, SDZ), a widely used sulfonamide antibiotic, in aqueous solution under electron beam irradiation was investigated to explore its potential as an Advanced Oxidation Process for environmental remediation. This study evaluated the effects of irradiation dose, initial sulfadiazine concentration, and initial pH on the degradation efficiency. It was found at 0.5 kGy that the degradation efficiency decreased with increasing initial SDZ concentration, from 83.0% at 5 mg/L to 35.0% at 30 mg/L. The kinetic results showed a pseudo-first order model. The degradation efficiencies of 30 mg/L SDZ reached 80.8%, 75.3%, 69.5% and 69.8%, respectively, at pH 3.0, 6.3, 9.0, and 11.0 at 3.0 kGy, indicating the pH dependence to SDZ degradation under electron beam. The maximum removal efficiency was around 90% after UV analysis and 99% after HPLC analysis for 10mg/L SDZ at absorbed doses of 2–3 kGy and pH 6.3. Increasing the degradation efficiency of 10 mg/L SDZ from 0.5 kGy to 3.0 kGy showed the dose dependence on SDZ removal. Reactive species generated during irradiation, including hydroxyl radicals, hydrogen radicals, and solvated electrons, were identified as primary contributors to the degradation process. The effect of reactive species on the degradation of 10 mg/L SDZ was evaluated at variable doses, revealing the following trend: $•OH>•\mathrm{H}>{\mathrm{e}}_{\mathrm{a}\mathrm{q}}^{-}$. Transformation products were characterized using high-performance liquid chromatography (HPLC) and mass spectrometry (MS), providing insights into the degradation pathway. The results demonstrate that electron beam irradiation is an effective and sustainable method for sulfadiazine removal in water treatment systems, offering an innovative approach to mitigating antibiotic pollution in aquatic environments. Full article

Background/Objectives: The pulmonary administration of antibiotics can be advantageous in treating pulmonary infections by promoting high intrapulmonary drug concentrations with reduced systemic exposure. However, limited benefits have been observed for pulmonary administration versus other administration routes due to its rapid clearance from the lung. Here, the effects of structural modifications on the epithelial permeability and antibacterial potency of a third-generation cephalosporin were investigated to improve the understanding of drug properties that promote intrapulmonary retention and how they may impact efficacy. Methods: Ceftazidime was modified by attaching 18 hydrophobic, hydrophilic, and mucus-binding motifs to the carboxylic acid distant from the beta-lactam by amidation. Epithelial permeability was investigated by drug transport assays using human bronchial epithelial air–liquid interface cultures. Antibacterial potency was determined by microtiter MIC assays with B. pseudomallei, P. aeruginosa, E. coli, and S. aureus. Results: A 40–50% reduction in the transepithelial transport rate was exhibited by two PEGylated ceftazidime analogs (mPEG8- and PEG5-pyrimidin-2-amine-ceftazidime) and n-butyl-ceftazidime. An increase in the transport rate was exhibited by four analogs bearing small and hydrophobic or negatively charged motifs (n-heptane-, phenyl ethyl-, glutamic acid-, and 4-propylthiophenyl boronic acid-ceftazidime). The antibacterial potency was reduced by ≥10-fold for most ceftazidime analogs against B. pseudomallei, P. aeruginosa, and E. coli but was retained by seven ceftazidime analogs primarily bearing hydrophobic motifs against S. aureus. Conclusions: The covalent conjugation of PEGs with MW > 300 Da reduced the epithelial permeability of ceftazidime, but these modifications severely reduced antibacterial activity. To improve the pulmonary retention of antibiotics with low membrane permeability, this work suggests future molecular engineering studies to explore high-molecular-weight prodrug strategies. Full article

Enterohemorrhagic Escherichia coli (EHEC) is a significant public health concern due to its ability to form biofilms, enhancing its resistance to antimicrobials and contributing to its persistence in food processing environments. Traditional antibiotics often fail to target these biofilms effectively, leading to increased bacterial resistance. This study aims to explore the efficacy of novel antibiofilm agents, specifically halogenated pyrimidine derivatives, against EHEC. We screened pyrimidine and 31 halogenated pyrimidine derivatives for their antimicrobial and antibiofilm activities against EHEC using biofilm quantification assays, SEM analysis, motility, and curli production assessments. Our findings reveal that certain halogenated pyrimidine derivatives, notably 2-amino-5-bromopyrimidine (2A5BP), 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (2A4CPP), and 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2,4DC5IPP) at 50 µg/mL, exhibited significant inhibitory effects on EHEC biofilm formation without affecting bacterial growth, suggesting a targeted antibiofilm action. These compounds effectively reduced curli production and EHEC motility, essential factors for biofilm integrity and development. qRT-PCR analysis revealed that two active compounds downregulated the expression of key curli genes (csgA and csgB), leading to reduced bacterial adhesion and biofilm formation. Additionally, in silico ADME–Tox profiles indicated that these compounds exhibit favorable drug-like properties and lower toxicity compared with traditional pyrimidine. This study highlights the potential of halogenated pyrimidine derivatives as effective antibiofilm agents against EHEC, offering a promising strategy for enhancing food safety and controlling EHEC infections. The distinct mechanisms of action of these compounds, particularly in inhibiting biofilm formation and virulence factors without promoting bacterial resistance, underscore their therapeutic potential. Full article

Staphylococcus aureus, prevalent in hospital and community settings, forms biofilms that are highly resistant to antibiotics and immune responses, complicating treatment and contributing to chronic infections. These challenges underscore the need for novel treatments that target biofilm formation and effectively reduce bacterial virulence. This study investigates the antibiofilm and antimicrobial efficacy of novel halogenated pyrimidine derivatives against S. aureus, focusing on three compounds identified as potent biofilm inhibitors: 2,4-dichloro-5-fluoropyrimidine (24DC5FP), 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (24DC5BPP), and 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (24DC5IPP). The three active compounds are bacteriostatic. In particular, 24DC5FP at 5 µg/mL achieved a 95% reduction in hemolysis with a minimum inhibitory concentration (MIC) of 50 µg/mL. Interestingly, 24DC5FP increased cell size and produced wrinkled colonies. qRT-PCR analysis showed that 24DC5FP suppressed the gene expressions of agrA and RNAIII (quorum sensing regulator and effector), hla (α-hemolysin), nuc1 (nucleases nuc1), and saeR (S. aureus virulence regulator). These findings suggest that extensive halogenation enhances the antibiofilm and antivirulence activities of pyrimidine derivatives, offering a promising strategy for combatting S. aureus infections, including those resistant to conventional treatments. Full article

Moxifloxacin (MOX), a widely used novel antibiotic, may pose ecological risks at its actual environmental concentrations, as has been detected in aquatic systems. However, its ecotoxicity to aquatic organisms and regulatory mechanisms of phosphorus in eutrophic aqueous environments are still limited. This study aimed to analyze its physiological and biochemical parameters, including cellular growth, chlorophyll fluorescence, photosynthetic pigments, oxidative stress biomarkers, and metabolomics to elucidate the toxicity induced by environmental concentrations of MOX in Microcystis aeruginosa at different phosphorus levels. The results revealed that the EC₅₀ values of MOX on M. aeruginosa at different phosphorus concentrations were 8.03, 7.84, and 6.91 μg/L, respectively, indicating MOX toxicity was exacerbated with increasing phosphorus levels. High phosphorus intensified the suppression of chlorophyll fluorescence and photosynthetic pigments, while activating the antioxidant enzyme, indicating severe peroxidation damage. Metabolomic analysis showed MOX induced different discriminating metabolites under different phosphorus levels, and perturbed more biological pathways at higher phosphorus concentrations, such as starch and sucrose metabolism, pyrimidine metabolism, and glycerolipid metabolism. This indicates that phosphorus plays an important role in regulating metabolism in M. aeruginosa exposed to MOX. The findings provide valuable information on the mechanisms involved in cyanobacteria responses to antibiotic stress, and offer a theoretical basis for accurately assessing antibiotic toxicity in eutrophic aqueous environments. Full article

In this study, we investigated the preparation of char and activated carbon (ACs) materials derived from water bottle waste collected from waste collection point in Tunis. The materials were synthesized using a rotary horizontal furnace on a lab/pilot scale and through chemical activation. Characterization of the carbon materials was performed using nitrogen adsorption isotherms at 77K and SEM-EDX analysis. Furthermore, we examined the effectiveness of the ACs in removing the antibiotics 4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide (sulfamethoxazole-C₁₀H₁₁N₃O₃S) and 5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine (trimethoprim) from aqueous solutions. The results revealed a maximum adsorption capacity of 108.17 mg g⁻¹ (85.34%) for sulfamethoxazole and 98.11 mg g⁻¹ (89.73%) for trimethoprim on the PET-KOH-1:1-800 °C sample. Additionally, we analyzed the adsorption kinetics, fitting the data to pseudo-first and -second-order models, and studied the equilibrium isotherms using the Langmuir and Freundlich equation models. These findings suggest significant potential for the application of ACs derived from plastic bottle waste in the treatment of wastewater containing antibiotics. Overall, our study highlights the feasibility of utilizing waste materials for the synthesis of valuable carbon-based adsorbents with promising adsorption capabilities. This research contributes to the ongoing efforts towards sustainable waste management and environmental remediation. Full article

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants. Full article

Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas in which pyrimidines have had a major impact in drug discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, and diabetes mellitus. The article presents the synthesis of the medicinal agents and highlights the role of the biological target with respect to the disease model. Additionally, the biological potency, ADME properties and pharmacokinetics/pharmacodynamics (if available) are discussed. This survey attempts to demonstrate the versatility of pyrimidine-based drugs, not only for their potency and affinity but also for the improved medicinal chemistry properties of pyrimidine as a bioisostere for phenyl and other aromatic π systems. It is hoped that this article will provide insight to researchers considering the pyrimidine scaffold as a chemotype in future drug candidates in order to counteract medical conditions previously deemed untreatable. Full article

The aim of this study is to propose a successful method for the treatment of water contaminated by pharmaceutical pollutants through homogeneous photocatalysis in the presence of decatungstate ions (W₁₀O₃₂⁴⁻). Sulfamethazine (SMZ), a sulfonamide antibiotic, was used as a model molecule. The results showed that SMZ could be effectively degraded with this process under simulated solar irradiation. SMZ degradation kinetics were studied with different dioxygen and SMZ concentrations, pH values, and photocatalyst masses. Optimal conditions were determined to be pH 7, [Na₄W₁₀O₃₂] = 0.33 g/L, and [SMZ] = 13.9 mg/L under the aerated condition, resulting in 85% SMZ degradation in 240 min, using a 36W-UVA/UVB light source. Hydroxyl radicals were identified as the major contributors to SMZ elimination. Four photoproducts identified with high-performance liquid chromatography coupled with mass spectrometry were formed by the cleavage of the sulfonamide bond and the hydroxylation of both the aromatic ring and pyrimidine moiety. SMZ was completely mineralized after 90 h of irradiation in the presence of decatungstate anions. These results provided a mechanism for the photocatalytic degradation of SMZ in an aqueous solution. To sustain this mechanism, theoretical studies were carried out using density functional theory calculations. This involved Fukui functional analyses, including ring hydroxylation, C-S bond cleavage, and molecular rearrangement processes. Full article

Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR⁺ lung cancer. Full article

Staphylococcus aureus is one of the major pathogens causing bovine mastitis, and antibiotic treatment is most often inefficient due to its virulence and antibiotic-resistance attributes. The development of new antibiotics for veterinary use should account for the One Health concept, in which humans, animals, and environmental wellbeing are all interconnected. S. aureus can infect cattle and humans alike and antibiotic resistance can impact both if the same classes of antibiotics are used. New effective antibiotic classes against S. aureus are thus needed in dairy farms. We previously described PC1 as a novel antibiotic, which binds the S. aureus guanine riboswitch and interrupts transcription of essential GMP synthesis genes. However, chemical instability of PC1 hindered its development, evaluation, and commercialization. Novel PC1 analogs with improved stability have now been rationally designed and synthesized, and their in vitro and in vivo activities have been evaluated. One of these novel compounds, PC206, remains stable in solution and demonstrates specific narrow-spectrum activity against S. aureus. It is active against biofilm-embedded S. aureus, its cytotoxicity profile is adequate, and in vivo tests in mice and cows show that it is effective and well tolerated. PC206 and structural analogs represent a promising new antibiotic class to treat S. aureus-induced bovine mastitis. Full article

Bacterial infections have attracted the attention of researchers in recent decades, especially due to the special problems they have faced, such as their increasing diversity and resistance to antibiotic treatment. The emergence and development of the SARS-CoV-2 infection stimulated even more research to find new structures with antimicrobial and antiviral properties. Among the heterocyclic compounds with remarkable therapeutic properties, benzimidazoles, and triazoles stand out, possessing antimicrobial, antiviral, antitumor, anti-Alzheimer, anti-inflammatory, analgesic, antidiabetic, or anti-ulcer activities. In addition, the literature of the last decade reports benzimidazole-triazole hybrids with improved biological properties compared to the properties of simple mono-heterocyclic compounds. This review aims to provide an update on the synthesis methods of these hybrids, along with their antimicrobial and antiviral activities, as well as the structure–activity relationship reported in the literature. It was found that the presence of certain groups grafted onto the benzimidazole and/or triazole nuclei (-F, -Cl, -Br, -CF₃, -NO₂, -CN, -CHO, -OH, OCH₃, COOCH₃), as well as the presence of some heterocycles (pyridine, pyrimidine, thiazole, indole, isoxazole, thiadiazole, coumarin) increases the antimicrobial activity of benzimidazole-triazole hybrids. Also, the presence of the oxygen or sulfur atom in the bridge connecting the benzimidazole and triazole rings generally increases the antimicrobial activity of the hybrids. The literature mentions only benzimidazole-1,2,3-triazole hybrids with antiviral properties. Both for antimicrobial and antiviral hybrids, the presence of an additional triazole ring increases their biological activity, which is in agreement with the three-dimensional binding mode of compounds. This review summarizes the advances of benzimidazole triazole derivatives as potential antimicrobial and antiviral agents covering articles published from 2000 to 2023. Full article