Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of
Xukai Jiang1, Kai Yang2, Bing Yuan2
1Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Melbourne, Australia.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Polymyxins like colistin A penetrate the outer membrane of Acinetobacter baumannii by disrupting lipid A interactions. This atomic-level understanding aids in developing new antibiotics against drug-resistant bacteria.
Area of Science:
- Microbiology
- Biophysics
- Computational Chemistry
Background:
- Multidrug-resistant (MDR) bacteria pose a global health threat.
- Polymyxins are crucial last-resort antibiotics against Gram-negative 'superbugs' like Acinetobacter baumannii.
- The atomic-level mechanism of polymyxin interaction with bacterial outer membranes is not fully understood.
Purpose of the Study:
- To elucidate the atomic-level structure-interaction relationship and thermodynamics of polymyxin penetration into the Acinetobacter baumannii outer membrane.
- To investigate the binding and conformational changes of polymyxins within the outer membrane.
Main Methods:
- Construction of a lipid A-based outer membrane model of A. baumannii using quantitative lipidomics data.
- Application of all-atom molecular dynamics simulations with umbrella sampling techniques.
Main Results:
- Polymyxins bind to the outer membrane via electrostatic interactions with lipid A, displacing cations.
- Polymyxins adopt a folded conformation upon entering the hydrophobic core, causing local membrane disorganization.
- This process increases membrane permeability, facilitating further polymyxin penetration.
Conclusions:
- Novel insights into the atomic and membrane-level thermodynamics of polymyxin penetration were obtained.
- The findings provide a foundation for designing new polymyxins against MDR Gram-negative pathogens.
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