Predictive compound accumulation rules yield a broad-spectrum antibiotic

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. The authors use computational modelling and a set of chemically synthesized compounds to define the physicochemical properties required for small-molecule accumulation in Gram-negative bacteria. Most small molecules are unable to cross the outer membrane of Gram-negative bacteria and accumulate inside these cells, which poses a challenge for the discovery of new drugs that target Gram-negative pathogens. By examining a set of chemically diverse small molecules, Paul Hergenrother and colleagues have now defined the physicochemical properties required for small-molecule accumulation in the Gram-negative bacteria Escherichia coli. They find that small molecules containing an amine, and which are amphiphilic, rigid and have low globularity, are most likely to be successful. They then apply these guidelines to convert a compound that targets Gram-positive bacteria only into a broad-spectrum antibiotic that is active against several Gram-negative pathogens.