Computational investigation of natural compounds as inhibitors against macrolide-resistant protein using virtual screening, molecular docking and MD simulations.

Macrolide resistance is the ability of bacteria to survive the effects of macrolide antibiotics, which include drugs such as erythromycin, clarithromycin, and azithromycin. Efforts to combat resistance mechanisms like this frequently involve the discovery and development of new antibiotics or therapeutic strategies capable of overcoming these modifications and restoring the efficacy of current antibiotics. In this study, we explored natural products against enzymes of macrolide resistance Macrolide 2'-phosphotransferase type I (mphA or ErmE), Macrolide 2'-phosphotransferase type II (mphB), Tripartite macrolide-specific efflux pump, Erythromycin esterase EreC, and rRNA methyltransferase (ErmAM) by molecular modelling techniques. The standard precision protocol of the Glide tool was utilized to dock a library of 1,400 natural product compounds from the LOTUS database against various enzymes associated with macrolide resistance. The docking results were assessed using the glide score, and the top ten compounds that were docked to each receptor were selected. Additionally, these selected compounds underwent ADMET analysis, suggesting their potential for therapeutic development. Among the selected compounds, LTS0271681 showed the highest binding affinity against ErmAM, LTS0263188 showed highest binding affinity against Tripartite macrolide-specific efflux pump, LTS0024216 showed the highest binding affinity against mphA, LTS0110759 showed the highest binding affinity against mphB, and LTS0100971 showed the highest binding affinity against EreC. The study incorporated molecular dynamic simulations and MM-GBSA binding free energy calculations to enhance the docking experiments. The results indicate that these compounds could potentially serve as inhibitors of macrolide resistance. However, while computational validations were part of this research, additional in-vitro studies are necessary to develop these potential inhibitors into therapeutic drugs.