In Silico-Based Discovery of Natural Anthraquinones with Potential against Multidrug-Resistant E. coli .
Hani A AlhadramiWesam H AbdulaalHossam M HassanNabil Abdulhafiz AlhakamyAhmed M SayedPublished in: Pharmaceuticals (Basel, Switzerland) (2022)
E. coli is a Gram-negative bacterium that causes different human infections. Additionally, it resists common antibiotics due to its outer protective membrane. Natural products have been proven to be efficient antibiotics. However, plant natural products are far less explored in this regard. Accordingly, over 16,000 structures covering almost all African medicinal plants in AfroDb in a structural-based virtual screening were used to find efficient anti- E. coli candidates. These drug-like structures were docked into the active sites of two important molecular targets (i.e., E. coli 's Ddl-B and Gyr-B). The top-scoring hits (i.e., got docking scores < -10 kcal/mol) produced in the initial virtual screening (0.15% of the database structures for Ddl-B and 0.17% of the database structures for Gyr-B in the database) were further refined using molecular dynamic simulation-based binding free energy (Δ G ) calculation. Anthraquinones were found to prevail among the retrieved hits. Accordingly, readily available anthraquinone derivatives (10 hits) were selected, prepared, and tested in vitro against Ddl-B, Gyr-B, multidrug-resistant (MDR) E. coli , MRSA, and VRSA. A number of the tested derivatives demonstrated strong micromolar enzyme inhibition and antibacterial activity against E. coli , MRSA, and VRSA, with MIC values ranging from 2 to 64 µg/mL. Moreover, both E. coli 's Ddl-B and Gyr-B were inhibited by emodin and chrysophanol with IC 50 values comparable to the reference inhibitors (IC 50 = 216 ± 5.6, 236 ± 8.9 and 0.81 ± 0.3, 1.5 ± 0.5 µM for Ddl-B and Gyr-B, respectively). All of the active antibacterial anthraquinone hits showed low to moderate cellular cytotoxicity (CC 50 > 50 µM) against human normal fibroblasts (WI-38). Furthermore, molecular dynamic simulation (MDS) experiments were carried out to reveal the binding modes of these inhibitors inside the active site of each enzyme. The findings presented in this study are regarded as a significant step toward developing novel antibacterial agents against MDR strains.
Keyphrases
- multidrug resistant
- escherichia coli
- gram negative
- drug resistant
- acinetobacter baumannii
- klebsiella pneumoniae
- endothelial cells
- high resolution
- staphylococcus aureus
- adverse drug
- methicillin resistant staphylococcus aureus
- silver nanoparticles
- risk assessment
- gene expression
- binding protein
- high intensity
- molecular dynamics
- emergency department
- cystic fibrosis
- single molecule
- human health
- anti inflammatory
- essential oil
- extracellular matrix