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

Alexis M. Stoorza, Adam S. Duerfeldt

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

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 languageEnglish (US)
Pages (from-to)65-80
Number of pages16
JournalJournal of medicinal chemistry
Volume67
Issue number1
DOIs
StatePublished - Jan 11 2024

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Review

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