Physicochemical and Structural Parameters Contributing to the Antibacterial Activity and Efflux Susceptibility of Small Molecule Inhibitors of Escherichia coli.

Physicochemical and Structural Parameters Contributing to the Antibacterial Activity and Efflux Susceptibility of Small Molecule Inhibitors of Escherichia coli. Antimicrob Agents Chemother. 2021 Jan 19;: Authors: El Zahed SS, French S, Farha MA, Kumar G, Brown ED Abstract Discovering new Gram-negative antibiotics has been a challenge for decades. This has been largely attributed to a limited understanding of the molecular descriptors governing Gram-negative permeation and efflux evasion. Herein, we address the contribution of efflux using a novel approach that applies multivariate analysis, machine learning, and structure-based clustering to some 4,500 actives from a small molecule screen in efflux-compromised Escherichia coli We employed principal-component analysis and trained two decision tree-based machine learning models to investigate descriptors contributing to the antibacterial activity and efflux susceptibility of these actives. This approach revealed that the Gram-negative activity of hydrophobic and planar small molecules with low molecular stability is limited to efflux-compromised E. coli Further, molecules with reduced branching and compactness showed increased susceptibility to efflux. Given these distinct properties that govern efflux, we developed the first machine learning model, called Susceptibility to Efflux Random Forest (SERF), as a tool to analyze the molecular descriptors of small molecules and predict those ...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research