Defining new chemical space for drug penetration into Gram-negative bacteria

Nat Chem Biol. 2020 Dec;16(12):1293-1302. doi: 10.1038/s41589-020-00674-6. Epub 2020 Nov 16.


We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge. In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addition to active drug efflux, making this cell envelope impermeable to most compounds. Second, chemical libraries currently used in drug discovery contain few compounds that can penetrate Gram-negative bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chemical space that are specifically relevant to antibacterial drug discovery. Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective analysis of chemical libraries for the ability of compounds to accumulate in Gram-negative bacteria. The overall goal is to develop robust cheminformatic tools to predict Gram-negative permeation and efflux, which can then be used to guide medicinal chemistry campaigns and the design of antibacterial discovery libraries.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Biological Transport
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Cell Membrane Permeability
  • Cheminformatics / methods*
  • Chemistry, Pharmaceutical
  • Computer Simulation
  • Drug Discovery
  • Drug Resistance, Multiple, Bacterial
  • Gram-Negative Bacteria / chemistry
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / metabolism
  • Humans
  • Models, Statistical*
  • Porins / chemistry
  • Porins / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Anti-Bacterial Agents
  • Porins
  • Small Molecule Libraries