Towards Understanding Antibiotic Permeation Across The Gram-negative Bacteria Outer Membrane Using Molecular Dynamics Simulations*

Permeation of antibiotics through the Gram-negative bacterial cell envelope is a complex process. Specifically, the outer membrane serves as an effective permeability barrier. To shed light on the energetics of antibiotic permeation across the outer membrane, we employed a molecular dynamics (MD) simulation approach to obtain the free energy profiles as various clinically important antibiotics were pulled across an Escherichia coli outer membrane model. Here, we deliver the first reported free energy estimates of erythromycin, gentamicin, novobiocin, rifampicin, and tetracycline as they cross the asymmetric outer membrane. While all antibiotics free energy curves have similar trends, the relative free energy barriers could be significantly different when each antibiotic permeates the outer membrane. Our results allow ranking of the outer membrane permeability of various antibiotics based on their free energy and diffusion coefficient values along with different segments of the asymmetric outer membrane. These detailed findings of drug/membrane interactions provide critical insights for understanding drug permeation and efficacy against Gram-negative bacteria such as E. coli.