RESUMEN
The increased multidrug resistance in Acinetobacter baumannii (A. baumannii) to the present-day known antibiotics has stimulated academic and industrial efforts globally for the development of novel antibacterial agents. Natural compounds as potential drug leads are gaining significant attention due to their less toxic and more tolerant nature. In the current study, the natural product-based compounds were explored as probable inhibitors of UDP-N-acetylmuramoyl-L-alanine:D-glutamate (MurD) ligase from A.baumannii (AbMurD) to provide a new class of drug leads. The prepared natural library of 3,16,714 compounds from ZINC database was screened into the active site of AbMurD using in silico high-throughput virtual screening which resulted in 100 compounds having high binding affinities. Further screening through flexible molecular docking yielded four potential compounds selected on the basis of estimated binding affinity (ΔG) and favorable protein-ligand interactions. MD simulation of these four compounds under physiological conditions and free binding energy calculations using MM/PBSA (molecular mechanics with Poisson- Boltzmann and surface area solvation) approach revealed three compounds ZINC08879777, ZINC30726863, and ZINC95486217 as potential binders of AbMurD. The calculated physicochemical and ADME properties of these compounds revealed that they can be exploited and modified to improve their binding affinity with the enzyme. Two compounds were purchased and tested against bacterial cell cultures of A. baumannii, Salmonella Typhi, and Staphylococcus aureus to determine their broad-spectrum antibacterial activity. The results suggest that the identified compounds can be exploited as potential herbal leads to target both Gram-positive and Gram-negative pathogens. Communicated by Ramaswamy H. Sarma.
Asunto(s)
Acinetobacter baumannii , Simulación del Acoplamiento Molecular , Acinetobacter baumannii/metabolismo , Simulación de Dinámica Molecular , Antibacterianos/química , Ligasas/metabolismoRESUMEN
Drug repurposing is an efficient alternative approach to counter the increasing drug-resistant pathogens to treat infectious diseases. FtsZ is an essential bacterial cytokinesis protein involved in the formation of cell-division complex and targeting FtsZ using FDA approved drugs is a promising strategy to identify and develop a new antibacterial drug. Using in silico pharmacophore-based screening of drug bank, molecular docking and molecular dynamics simulations, we identified six drugs inhibiting the function of stFtsZ from Salmonella Typhi. The selected drugs target stFtsZ at the hydrophobic cleft formed between the C-terminal domain and helix α7 with binding energy better than -8 kcal/mol. Out of these six drugs, benzethonium chloride showed promising results at 8 µM concentration where it inhibits stFtsZ GTPase activity by 80% and prevents polymerization. Benzethonium chloride also possesses an excellent antibacterial activity against the bacterial culture of Salmonella Typhi (ATCC 19430), Staphylococcus aureus (ATCC 43300) and Escherichia coli (ATCC 25922) with the MIC values of 8 µg/mL, 1 µg/mL and 12 µg/mL, respectively. Based on our current study, the scaffold of benzethonium chloride can be used for the development of broad-spectrum antibacterial agents against drug-resistant pathogens.