Targeting of the Gram-Negative Outer Membrane for Antibiotic Discovery and Potentiation

The emergence of multidrug resistance underscores the urgent need to develop new classes of antibiotics with novel mechanisms of action. The majority of antibiotics currently in use are designed to target Gram-positive bacteria. However, Gram-negative bacteria can circumvent the effects of the majority of drug molecules due to the unique composition of their outer membrane. This additional layer functions as a formidable barrier, impeding the penetration of compounds into the cell. In this context, several strategies have been identified to facilitate the accumulation of compounds in Gram-negative bacteria. This review provides a concise overview of the physicochemical properties that can assist in the entry and accumulation of compounds in Gram-negative bacteria, and it also covers various approaches for targeting or circumventing the outer membrane-mediated barrier of Gram-negative pathogenic bacteria.