Predictive compound accumulation rules yield a broad-spectrum antibiotic

Abstract

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 for these pathogens very challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negatives is largely based on retrospective analyses of antibacterials that suggest polarity and molecular weight as 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 these findings will aid in the discovery and development of antibiotics effective against Gram-negative bacteria.

Identification and Structure–Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli

“…The latter two properties, along with low globularity and the presence of an unhindered basic nitrogen, were recently shown to be favorable for antibiotic accumulation in Gram-negative bacteria. 31 These compounds fall nicely within the favorable property range for crossing the OM of Gram-negative bacteria (See Supplemental Material, Table 2S), which is consistent with our own experimental data. Additionally, with the reduced MW we have the flexibility to optimize these molecules for binding to AcrA, antibacterial targets, or introduce additional modifications to the cinnamoyl group to mitigate potential risk while remaining in the optimal chemical space.…”

The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile

“…58 Recent studies on drug transport in Gram-negative bacteria have shown that changes in drug structure can convert an agent that is selective for Gram-positive into one that works on Gram-negative agents by facilitating transport. 59 …”

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

“…Gram-positive antibiotic deoxynybomycin expanded its antimicrobial activity to multi-drugresistant Gram-negative pathogenic strains 9 . Therefore, we hypothesised that violacein analogues with similar features could also have the potential to have improved activity against resistant strains.…”