The challenge of converting gram-positive-only compounds into broad-spectrum antibiotics

Michelle F. Richter, Paul Hergenrother

Research output: Contribution to journalReview article

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18-38
Number of pages21
JournalAnnals of the New York Academy of Sciences
Volume1435
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Anti-Bacterial Agents
Escherichia coli
Gram-Negative Bacterial Infections
Guidelines
Pathogens
Gram-Negative Bacteria
Pharmaceutical Preparations
Lenses
Amines
Bacteria
Nitrogen
Retrospective Studies
Derivatives
Molecules
Antibiotics
Research
Drugs
Datasets
Rise
Infection

Keywords

  • Antibacterials
  • Gram-negative bacteria
  • Molecular properties
  • Multidrug resistance

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

The challenge of converting gram-positive-only compounds into broad-spectrum antibiotics. / Richter, Michelle F.; Hergenrother, Paul.

In: Annals of the New York Academy of Sciences, Vol. 1435, No. 1, 01.01.2019, p. 18-38.

Research output: Contribution to journalReview article

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