Elucidating Antibiotic\nPermeation through the Escherichia coli Outer Membrane: Insights from Molecular\nDynamics

Antibiotic resistance represents a critical public health\nthreat,\nwith an increasing number of Gram-negative pathogens demonstrating\nresistance to a broad range of clinical drugs. A primary challenge\nin enhancing antibiotic efficacy is overcoming the robust barrier\npresented by the bacterial outer membrane. Our research addresses\na longstanding question: What is the rate of antibiotic permeation\nacross the outer membrane (OM) of Gram-negative bacteria? Utilizing\nmolecular dynamics (MD) simulations, we assess the passive permeability\nprofiles of four commercially available antibioticsgentamicin,\nnovobiocin, rifampicin, and tetracycline across an asymmetric atomistic\nmodel of the Escherichia coli (E. coli) OM, employing the inhomogeneous solubility-diffusion\nmodel. Our examination of the interactions between these drugs and\ntheir environmental context during OM permeation reveals that extended\nhydrogen bond formation and drug–cation interactions significantly\nhinder the energetics of passive permeation, notably affecting novobiocin.\nOur MD simulations corroborate well with experimental data and reveal\nnew implications of solvation on drug permeability, overall advancing\nthe possible use of computational prediction of membrane permeability\nin future antibiotic discovery.