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bioRxiv · 10.1101/2025.02.28.640864

Targeting D-Ribose-Binding Proteins in Brucella melitensis: A Novel Frontier Against Antibiotic Resistance

Moradi, O.·Maghsoudi, A.·Masoudi, A. A.·Torshizi, R. V.
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Abstract

BackgroundAntibiotic resistance among pathogens common to human beings and animals, which include Brucella melitensis, has end up a significant worldwide health task. Traditional antibiotic treatments for brucellosis, along with lengthy-time period regimens of doxycycline and rifampicin, are going through increasing boundaries because of rising resistance, affected person adherence issues, and considerable side results. MethodsThis observe investigates the capacity of targeting the periplasmic D-ribose-binding protein (DBP), a key component of the bacterial ATP-binding cassette (ABC) delivery system, as a unique healing technique. Protein structural modeling was performed to use of superior computational tools together with AlphaFold, Swiss-Model, and Phyre2, followed by validation via Ramachandran plots and energy minimization techniques. Molecular docking analyses recognized D-Talopyranose as a promising ligand with a high binding affinity of -5.8 kcal/mol. Subsequent ADMET profiling found out favorable pharmacokinetic and toxicological results, assisting its potential as a drug candidate. Molecular dynamics simulations similarly evaluated the stability and dynamics of the protein-ligand interplay complex, confirming its suitability for therapeutic programs. ResultsAdvanced computational tools were used to analyze the proteins structure, and key modifications that influence its stability and function were identified. AlphaFold was recognized as the most reliable model for predicting the proteins 3D architecture, with its predictions being validated by metrics such as Ramachandran plots and error assessments. D-Talopyranose, a sugar molecule, was revealed as a top candidate through molecular docking due to its strong binding affinity with DBP. Promising drug-like properties, including balanced solubility, low toxicity risks, and minimal interactions with metabolic enzymes, were highlighted in further analysis, though environmental concerns around biodegradability were noted. The stability of the protein-ligand complex was tracked through simulations, showing consistent structural integrity despite minor flexibility in certain regions. While frequent dosing may be required due to the compounds rapid clearance from the body, its safety profile and synthetic accessibility are positioned as a viable starting point for drug development. Computational predictions are bridged with practical insights in this work, offering a roadmap for targeted therapies against antibiotic-resistant infections, while the need to balance efficacy with environmental safety in future optimizations is underscored. Our outcomes reveal that targeting DBP could offer a unique mechanism to combat antibiotic-resistant lines of Brucella melitensis by using disrupting essential metabolic pathways. ConclusionThis study affords a promising street for revolutionary brucellosis treatments by way of addressing the challenges posed using antibiotic resistance and paves the manner for experimental validation and optimization of the identified ligands. Such focused strategies may also notably improve ailment control and reduce the worldwide burden of brucellosis, mainly in areas where traditional antibiotics are losing their efficacy.

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Moradi, O., Maghsoudi, A., Masoudi, A. A., Torshizi, R. V.. 2025-03-06. Targeting D-Ribose-Binding Proteins in Brucella melitensis: A Novel Frontier Against Antibiotic Resistance. https://doi.org/10.1101/2025.02.28.640864

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