Tahane Bashir Mohammeddeen Ahmed

Antimicrobial resistance (AMR) is an emerging global health concern that demands the identification of novel drug targets and bioactive molecules to combat resistant bacterial pathogens. In the present study, AmvR, a TetR family transcriptional regulator, was studied as a putative potential drug target because of its critical role in bacterial adaptation and associated antimicrobial resistance mechanisms. A structure-based virtual screening approach (SBVS) was used to identify new inhibitors derived from marine sources available in the Comprehensive Marine Natural Products Database (CMNPD) and the Seaweed Metabolite Database (SWMD). The docking protocol was first validated using spermidine, the co-crystallized ligand (RMSD = 0.12 Å), after which approximately 32,200 marine natural products (MNPs) were screened against the AmvR binding site. Four MNPs (CMNPD9680, CMNPD23795, CMNPD5249, and SWMD-BS008) identified as the top-ranked candidates based on their docking score (ranging from −11.4 to −20.3 kcal/mol) and docking-stage MMGBSA binding energy estimates (ranging from −89.7 to −104.4 kcal/mol), compared with the control ligand. Pharmacokinetics and toxicity analyses indicated favorable drug-like and safety profiles for the selected MNPs. The structural stability of apo AmvR and the ligand-bound complexes was further evaluated through 500 ns molecular dynamics (MD) simulations. Analyses of RMSD, RMSF, Rg, SASA, hydrogen-bond dynamics, post-dynamics MM/PBSA binding free energies, principal component analysis (PCA), free energy landscape (FEL) mapping, and DSSP-based secondary structure evaluation consistently demonstrated the stability of the protein–ligand interactions throughout the simulation period. Among the identified MNPs, CMNPD9680 exhibited the highest binding affinity, the most favorable docking-stage MM/GBSA binding free energy, and a stable interaction network within the AmvR binding pocket. The structural similarity analysis based on Morgan fingerprints revealed that the shortlisted marine compounds have conserved features in common with experimentally validated antibacterial compounds against Acinetobacter baumannii, making them prospective antibacterial leads. Overall, these findings demonstrate the potential of marine natural products as promising AmvR inhibitors and identify CMNPD9680 as a promising computational candidate for further experimental investigation against A. baumannii.

Objective: Biofilm-caused catheter-associated urinary tract infections (CAUTIs) are of increasing concern due to their severe complications and rising morbidity rates. This underscores the urgent need for alternative antimicrobial agents for effective management. In this study, the ethanolic extract of Manihot esculenta waste was evaluated for its antibacterial, anti-adhesive and antibiofilm activities against two major bacterial pathogens forming biofilms on urinary catheters, viz. Enterococcus faecalis and Pseudomonas aeruginosa. Methods: The antibacterial activity of the extract was evaluated against E. faecalis and P. aeruginosa using the agar diffusion method, and the minimum inhibitory concentrations (MIC) was determined through the microdilution method. The phytochemicals were identified using Gas Chromatography and Mass Spectrometry (GC-MS). The antibiofilm activities were quantified after extract treatment through the crystal violet assay, and the anti-adhesive property of M. esculenta waste ethanolic extract-coated catheter tube was studied through in vitro bladder model. In silico docking analysis was carried out forcis-13, 16-docasadienoic acid, methyl ester against the important proteins involved in biofilm formation. The antioxidant activity of the extract was investigated using DPPH (2,2-diphenyl-1-picrylhydrazyl) assay and ABTS (2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assay. Results: The ethanolic extract of M. esculenta waste exhibited antibacterial activity against both test organisms. The minimum inhibitory concentration (MIC) was 1 mg/ml against E. faecalis and 2 mg/ml against P. aeruginosa. GC–MS analysis identified several phytoconstituents including sucrose, diethylene glycol adipate, hexadecanoic acid methyl ester, and cis-13,16-docosadienoic acid methyl ester as major compounds. Biofilm inhibition assays showed a concentration-dependent reduction in biofilm formation in both pathogens. At the tested concentrations, biofilm biomass decreased significantly compared with the untreated control. In mature biofilm eradication assays, the extract removed up to 88% of E. faecalis biofilms and 89% of P. aeruginosa biofilms. Molecular docking studies demonstrated that cis-13,16-docosadienoic acid methyl ester interacted with the selected biofilm-associated target proteins, exhibiting favourable binding energies and multiple hydrogen-bond and hydrophobic interactions. Catheter tubes coated with the extract produced distinct zones of inhibition against both bacterial strains, whereas uncoated catheter segments showed no inhibitory effect. In antioxidant assays, the extract exhibited dose-dependent free-radical scavenging activity. Cytotoxicity assessment using L929 fibroblast cells showed cell viability above the acceptable biocompatibility threshold across the tested concentration range. Conclusion: Collectively, the findings suggested that M. esculenta waste extract can serve as a promising alternative antibacterial agent for preventing and managing CAUTIs.

Background & objectives: Chikungunya is a re-emerging infectious disease. It is spreading rapidly in the eastern states of Sudan. Leading a large outbreak during 2018-2019. Chikungunya virus is transmitted by Aedes mosquitoes, which are endemic in Sudan. Despite its public health impact, no specific antiviral drugs are available. This Study was conducted to formulate the Mathematical model of Chikungunya virus spread between the vector and human, to understand the pattern of disease dynamics. Methods: In this study, we formed a model for the dynamics of Chikungunya virus propagation in human beings, as well as examining the qualitative mosquito population’s development. Furthermore, the fundamental reproduction number serves as the biological threshold criterion for this disease. Hence, using the next-generation matrix method to find basic reproduction numbers. Results: The model shows the conditions under which the disease persists or dies out, based on the value of reproduction number. Stability analysis shows that the disease-free equilibrium is stable when reproduction number less than one and unstable when reproduction number greater than one. Numerical simulations illustrate the transmission patterns and confirm the analytical findings using real epidemiological data. Interpretation & conclusion: The patterns revealed by the analytical and numerical results shed light on the spread of the disease in the Red Sea State. Some significant emphases and insights are offered in light of the results, which may aid in lowering the number of chikungunya infection cases.

Biofilm-associated prosthetic joint infections (PJIs) are becoming an increasing public health concern due to their ability to form biofilm on prosthetic implants and cause significant morbidity owing to antibiotics resistance. Therefore, new drugs and management procedures are required to improve the treatment outcome for PJIs and the drug repurposing is an excellent method to develop new antimicrobials. Thus, the present study evaluated etoricoxib, a selective COX2 inhibitor for its antibacterial and antibiofilm activities against Staphylococcus aureus – one of the major biofilm-forming bacteria causing the PJIs. The anti-S. aureus potential of etoricoxib was analyzed and the minimum inhibitory concentration (MIC) was found to be as low as 25 µg/mL. The killing-kinetics of etoricoxib was observed at 2 h and the drug showed synergistic effect along with ampicillin and tetracycline, reducing the MIC by 4-fold. Further, etoricoxib exhibited antibiofilm activity by inhibiting biofilm formation and displaying mature biofilm eradication by 90% after the treatment. To prevent biofilm formation on implant material, etoricoxib was coated on the implant material and it reduced 80% of bacterial attachment which was further confirmed by FDA/PI staining that revealed 79% of dead cells on the coated material. The docking analysis revealed the strong binding affinity of etoricoxib towards bacterial biofilm adhesion proteins and the drug downregulated the biofilm adhesion protein encoded genes namely icaA, clfA, cna, fnbA, and fib expression levels after the treatment. Moreover, etoricoxib treatment caused S. aureus cell damage resulting in cell death and was noticed through scanning electron microscope (SEM) analysis. Thus, as etoricoxib was effective in eliminating and preventing biofilms and the authors recommend further in vitro and in vivo studies to explore the possibility for new therapeutic option for implant-associated infections. Graphical abstract

Aim: Healthcare-associated infections (HAIs), especially when multidrug-resistant bacteria cause them, pose serious challenges resulting in higher healthcare expenses, increased morbidity, and higher mortality, and thus, there is a need for new antimicrobial agents. Repurposing an old drug for new applications is an important trend, and in the present study, an anti-breast cancer drug, Tamoxifen, has been screened alone and in combination with silver nanoparticles (AgNPs) synthesized using Abutilon indicum Linn. against Enterococcus faecalis, Escherichia coli, and Staphylococcus aureus, which are involved in HAIs. Methods: The drug and the combination were subjected to antimicrobial potential analysis and the determination of minimum inhibitory concentrations (MICs) by agar diffusion and microdilution methods. Biofilm formation assays were performed using the crystal violet method to understand biofilm prevention and eradication efficiencies. The synergism in the activities of the drug and the combination with selected antibiotics was studied using checkerboard assay, and the cytotoxic effects of the drug and the combination on L929 cells were analyzed using MTT assay. Results: Tamoxifen and the AgNPs showed promising antibacterial activities, and the MICs of the drug were found to be 62.5 µg/mL (E. coli), 31 µg/mL (S. aureus), and 125 µg/mL (E. faecalis). When combined with AgNPs, Tamoxifen showed a 4-fold reduction in the MIC. The drug also displayed promising antibiofilm activities as it reduced mature S. aureus biofilms by 91%, E. faecalis biofilms by 88%, and E. coli biofilms by 73%. AgNPs alone reduced 91%, 91%, and 81% of biofilms by S. aureus, E. faecalis, and E. coli, respectively, and the combination treatment revealed 92% of S. aureus, 94% of E. faecalis, and 82% of E. coli biofilm eradication at their MICs. Tamoxifen also showed synergism when combined with antibiotics—ampicillin and rifampicin and the AgNPs in combination with Tamoxifen revealed no cytotoxic effect on L929 cells at their MICs. Conclusions: All the mentioned studies suggest that Tamoxifen alone and in combination with AgNPs has promising antibacterial and anti-biofilm activities, and it can be developed for better treatment options against HAIs as they are safe for eukaryotic cells.