Molecular Dynamics Simulations of Pseudomonas aeruginosa Membranes Aid in Understanding Resistance Mechanism to Polymyxin B1

One of the major causes for hospital acquired infections is multidrug-resistant Pseudomonas aeruginosa strains. Polymyxins are a group of lipopeptide antibiotics used as a last-line resort for treatment of Gram-negative infections. Polymyxins initially target Lipid A’s of lipopolysaccharides in the bacterial outer membrane via both electrostatic and hydrophobic interactions. Resistance to polymyxins in P. aeruginosa includes modification of Lipid A’s to attenuate the interactions with polymyxins but to date our understanding of underlying mechanisms is still limited. This study was conducted to investigate the molecular mechanisms of Polymyxin B1 interacting with outer membranes of P. aeruginosa strains including wild-type strain PAK (Polymyxin B1 MIC = 1 mg/L) control and treated and PAKpmrB6 strain (MIC = 8 mg/L) control and treated. Molecular models of PAK as well as PAKpmrB6 membranes were established, and each of those four membrane compositions were simulated as eight independent simulation systems, excluding and including six Polymyxin B1 molecules. The created membrane systems were evaluated running Molecular Dynamic (MD) Simulations for up to 1150 ns each. MD simulations showed that different membrane compositions and Polymyxin B1 interaction affect the general membrane behaviour. In addition, Polymyxin B1 interacts with mutant PAKpmrB6 membranes more slowly and penetrates them less deeply compared to non-mutant membranes. In summary, MD simulations of different membrane compositions provide insights at the membrane level that are consistent with the observed difference in Polymyxin B1 susceptibility between the PAK and PAKpmrB6 strains.