Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Monday Speaker Abstracts

SIMULATING POLYMYXIN-INDUCED DIVALENT IONS DISPLACEMENT IN THE OUTER MEMBRANE OF GRAM-NEGATIVE BACTERIA Mariia Savenko 1,4 ; Robert Vácha 2,3 ; Christophe Ramseyer 4 ; Timothée Rivel 2,3 ; 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic 2 Masaryk University, Central European Institute of Technology, Brno, Czech Republic 3 Masaryk University, National Centre for Biomolecular Research, Brno, Czech Republic 4 Université de Bourgogne Franche-Comté, Laboratoire Chrono-environnement UMR CNRS 6249, Besançon, France Since their discovery over 75 years ago, polymyxins have undergone a remarkable journey in medicine. While they were recognized for their antimicrobial activity against Gram-negative bacteria, their nephro- and neurotoxicity led to their relegation as less toxic antibiotic classes went on the market. Later, the surge of multidrug-resistant bacterial strains brought them back as last-resort treatment. However, in the past decade, multiple resistance mechanisms against polymyxins were identified which set the clock to find alternative therapeutics. Polymyxins remain a rare category of drugs capable of permeabilizing the rigid and asymmetric lipopolysaccharide-containing outer membrane of Gram-negative bacteria without passing through protein channels. It is believed that polymyxins can affect the dense network of divalent ions that are known to bridge lipopolysaccharides in the outer leaflet together. However, it is still unclear how exactly that affects the outer membrane properties, and how important this is in polymyxins mode of action. In our work, we employed all-atom and coarse-grained molecular dynamics simulations to model the outer membrane of two resistant and one non-resistant strains of Salmonella enterica. We utilized enhanced sampling methods to investigate the local action of polymyxins on membrane-bound divalent cations. Additionally, we compared this local effect with global stress applied to the membrane, indicating that the action of polymyxins cannot be reduced to the local ions removal only. Our findings provide valuable insights into the role of ion displacement in outer membrane dynamics and its implications for polymyxins' permeabilization mechanism.

19