Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii.

Xukai Jiang,Nitin A Patil,Yan Zhu,Jingliang Li,Kai Yang,Falk Schreiber,Bin Gong,Lushan Wang,Kade D Roberts,Tony Velkov,Bing Yuan,Jian Li,Meiling Han,Robert E W Hancock

doi:10.1093/jac/dkaa376

Abstract

MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure-interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure-interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.

Highlights

The world is facing a serious health challenge due to antimicrobial resistance
The interaction of polymyxins with bacterial membranes has been investigated over the last few decades,[4,5,6,7] the exact mechanism by which polymyxins penetrate into the bacterial outer membrane (OM) remains unclear at the atomic scale
We developed an A. baumannii OM model using quantitative membrane lipidomics data[22] and employed all-atom Molecular dynamics (MD) simulations and umbrella sampling to elucidate how polymyxins interact with the OM of A. baumannii and the thermodynamics governing the penetration into the OM

Summary

Introduction

The WHO and government sectors have developed a global action plan to mitigate antimicrobial resistance.[1] MDR Acinetobacter baumannii is a problematic pathogen due to its resistance to almost all available antibiotics and sits atop the WHO priority pathogen list for research and development of new antibiotics.[2] Due to the lack of new antibiotics under development, polymyxins (i.e. polymyxin B and colistin; Figure 1a) are increasingly used as a last-line option against life-threatening Gram-negative pathogens, including A. baumannii.[3] the interaction of polymyxins with bacterial membranes has been investigated over the last few decades,[4,5,6,7] the exact mechanism by which polymyxins penetrate into the bacterial outer membrane (OM) remains unclear at the atomic scale. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level

Methods

Results

Conclusion