The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

Multidrug resistant Gram‐negative bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram‐negative species. Efforts to understand the molecular properties that enable certain compounds to accumulate in Gram‐negative bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small molecules to accumulate in Escherichia coli led to predictive guidelines for compound accumulation in E. coli. These “eNTRy rules” state that compounds are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three‐dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivatives and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram‐positive‐only compounds into broad‐spectrum antibiotics.