Guiding the Way: Traditional Medicinal Chemistry Inspiration for Rational Gram-Negative Drug Design

The discovery and development of small-molecule therapeutics effective against Gram-negative pathogens are highly challenging tasks. Most compounds that are active in biochemical settings fail to exhibit whole-cell activity. The major reason for this lack of activity is the effectiveness of bacterial cell envelopes as permeability barriers. These barriers originate from the nutrient-selective outer membranes, which act synergistically with polyspecific efflux pumps. Guiding principles to enable rational optimization of small molecules for efficient penetration and intracellular accumulation in Gram-negative bacteria would have a transformative impact on the discovery and design of chemical probes and therapeutics. In this Perspective, we draw on inspiration from traditional medicinal chemistry approaches for eukaryotic drug design to present a broader call for action in developing comparable approaches for Gram-negative bacteria.