A multidisciplinary approach towards identification of novel antibiotic scaffolds forAcinetobacter baumannii

Abstract

AbstractResearch efforts to discover potential new antibiotics for Gram-negative bacteria suffer from high attrition rates due to the synergistic action of efflux systems and the limited permeability of the outer membrane (OM). One potential strategy to overcome the OM permeability barrier is to identify small molecules that are natural substrates for abundant OM channels, and to use such compounds as scaffolds for the design of efficiently-permeating antibacterials. Here we present a multidisciplinary approach to identify such potential small-molecule scaffolds. Focusing on the pathogenic bacteriumAcinetobacter baumannii, we use OM proteomics to identify DcaP as the most abundant channel under various conditions that are relevant for infection. High-resolution X-ray structure determination of DcaP surprisingly reveals a trimeric, porin-like structure and suggests that dicarboxylic acids are potential transport substrates. Electrophysiological experiments and allatom molecular dynamics simulations confirm this notion and provide atomistic information on likely permeation pathways and energy barriers for several small molecules, including a clinically-relevant β-lactamase inhibitor. Our study provides a general blueprint for the identification of molecular scaffolds that will inform the rational design of future antibacterials.