Antibiotic Uptake Across Gram-Negative Outer Membranes: Better Predictions Towards Better Antibiotics

• DOI: 10.1021/acsinfecdis.9b00201
• Publication Date: 2019-10-08T22:46:23Z
• Authors: Ricardo J. Ferreira; Peter M. Kasson
• Keywords: Membrane permeability; Cell membrane; Gram-Negative Bacteria

Crossing the Gram-negative bacterial membrane poses a major barrier to antibiotic development, as many small molecules that can biochemically inhibit key processes are rendered microbiologically ineffective by their poor cellular uptake. The outer is permeability for drug-like molecules, and chemical properties enable efficient uptake into mammalian cells fail predict We have developed computational method accurate prospective prediction of which we combine with new medium-throughput experimental assay vesicle swelling. Parallel molecular dynamics simulations compound through Escherichia coli (E. coli) OmpF used successfully quantitatively permeabilities measured via either swelling or prior liposome-swelling measurements. These analyzed using an inhomogeneous solubility-diffusion model yield predictions permeability. For most polar test, also correlates well whole-cell ability accurately measure wide variety will simpler determination scaffolds derivatives promising extensive synthesis. It assist in formulating more systematic understanding determinants