Predictive compound accumulation rules yield a broad-spectrum antibiotic

Nature. 2017 May 18;545(7654):299-304. doi: 10.1038/nature22308. Epub 2017 May 10.


Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amines / metabolism
  • Amines / pharmacology
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism*
  • Anti-Bacterial Agents / pharmacology*
  • Biological Products / metabolism
  • Biological Products / pharmacology
  • Drug Design
  • Escherichia coli / cytology
  • Escherichia coli / drug effects
  • Escherichia coli / metabolism
  • Gram-Negative Bacteria / cytology
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / metabolism*
  • Gram-Positive Bacteria / drug effects
  • Microbial Viability / drug effects
  • Quinolones / metabolism
  • Quinolones / pharmacology


  • Amines
  • Anti-Bacterial Agents
  • Biological Products
  • Quinolones
  • deoxynybomycin