Atomistic insight and modeled elucidation of conessine towards Pseudomonas aeruginosa efflux pump

Abstract

Drug-resistant Pseudomonas aeruginosa efflux 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 from Holarrhena 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 PAβN 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 against P. aeruginosa.

Communicated by Ramaswamy H. Sarma

Keywords:

• Efflux pump inhibitor
• conessine
• molecular docking
• molecular dynamics simulation
• Pseudomonas aeruginosa

Acknowledgement

The author would like to credit Potjanee Srimanote, Thammasat University for the ignition of this project.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by TRF Senior Research Scholar (Grant No. RTA6180006), the Thailand Research Fund. JJ and VT would like to thank Faculty of Medicine, Prince of Songkla University for the postgraduate scholarships.