Abstract
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.
Original language | English (US) |
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Pages (from-to) | 65-80 |
Number of pages | 16 |
Journal | Journal of medicinal chemistry |
Volume | 67 |
Issue number | 1 |
DOIs | |
State | Published - Jan 11 2024 |
Bibliographical note
Publisher Copyright:© 2023 American Chemical Society.
PubMed: MeSH publication types
- Journal Article
- Review