Atomistic insight and modeled elucidation of conessine towardsPseudomonas aeruginosaefflux pump

Drug-resistantPseudomonas aeruginosaefflux pump extrudes antibiotics from cells for survival. Efflux pump inhibitor (EPI) thus becomes an interesting alternative to handle the drug-resistant bacteria. Conessine, a natural steroidal alkaloid fromHolarrhena antidysenterica, previously exhibited efflux pump inhibitory potential. Our molecular docking and molecular dynamics (MD) studies provided atomistic information as well as the interaction of conessine with bacterial MexB efflux pump in phospholipid bilayer membrane to further the previous experimental report. Herein, the binding site and proposed mode of action of conessine were identified compared to known/commercial EPIs such as PA beta N or designed-synthetic P9D. Our results explained conessine binding mode of action as an effective agent against the MexB efflux pump. The MD simulation also suggested that conessine was able to affect glycine loop (G-loop) flexibility, and the reduced G-loop flexibility due to conessine could hinder an antibiotics extrusion. In addition, our study suggested the conessine core structure buried in a hydrophobic region in the efflux pump similar to other known EPIs. Our finding could cope as a key for the design and development of the conessine derivative as novel EPI againstP. aeruginosa. Communicated by Ramaswamy H. Sarma

Automated summary

The study revealed the mechanism of action of conessine against Pseudomonas aeruginosa's efflux pump, including its impact on glycine loop flexibility and binding site in the efflux pump. This could serve as a key for designing and developing novel EPIs against multidrug-resistant P. aeruginosa.