2. Academic Validation
  3. Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation

Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation

  • Cell Chem Biol. 2019 Sep 19;26(9):1274-1282.e4. doi: 10.1016/j.chembiol.2019.06.002.
Scott McAuley 1,  Alan Huynh 1,  Alison Howells 2,  Chris Walpole 3,  Anthony Maxwell 4,  Justin R Nodwell 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada.
  • 2 Inspiralis Ltd., Innovation Centre, Norwich Research Park, Colney Lane, Norwich NR4 7UH, UK.
  • 3 Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
  • 4 Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
  • 5 Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada. Electronic address: justin.nodwell@utoronto.ca.
PMID: 31279606 DOI: 10.1016/j.chembiol.2019.06.002
Abstract

Common approaches to Antibiotic discovery include small-molecule screens for growth inhibition in target pathogens and screens for inhibitors of purified Enzymes. These approaches have a shared intent of seeking to directly target a vital Achilles heel in a pathogen of interest. Here, we report the first screen against a sporulation pathway in a non-pathogenic bacterium as a means of discovering novel antibiotics-this effort has resulted in two important discoveries. First, we show that the sporulation program of Streptomyces venezuelae is exquisitely sensitive to numerous forms of DNA damage. Second, we have identified a DNA gyrase inhibitor. This molecule, EN-7, is active against pathogenic species that are resistant to ciprofloxacin and other clinically important Antibiotics. We suggest that this strategy could be applied to other morphogenetic pathways in prokaryotes or eukaryotes as a means of identifying novel chemical matter having scientific and clinical utility.

Keywords

DNA gyrase inhibitors; antibiotic; antibiotic resistance; chemical screening; discovery; sporulation inhibitors; target identification.

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