Structural Properties of β-Lactamese Inhibitors: Computational Study to Enhance Permeability through General Porins of Gram-Negative Bacteria

The rapid development of resistance to many current antibiotics in numerous pathogenic bacterial strains represents an urgent global public health problem. Therefore, we need to develop alternative strategies for the development of new molecules characterized by appropriate therapeutic properties. Gram-negative bacteria, in particular, represent an important challenge because of their external membrane, which represents an additional barrier against any molecular species. This work is focused on understanding of the physico-chemical parameters that govern the permeation process of β-lactamase inhibitors through porins, (the main pathway for the entry into Gram negative bacteria) in order to design/optimize antibacterials with improved efficacy. Molecular Dynamics (MD) simulations combined with the enhanced sampling technique Well-Tempered Metadynamics (WT-METAD) provided important details, at the atomic level, on the interactions between the permeating molecules and these protein channels and allowed to overcome limitations of experimental techniques.