2. Academic Validation
  3. Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis

Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis

  • Nat Chem Biol. 2022 Aug 22. doi: 10.1038/s41589-022-01102-7.
Yu Imai  # 1 2,  Glenn Hauk  # 3,  Jeffrey Quigley 1,  Libang Liang 1,  Sangkeun Son 1,  Meghan Ghiglieri 1,  Michael F Gates 1,  Madeleine Morrissette 1,  Negar Shahsavari 1,  Samantha Niles 1,  Donna Baldisseri 4,  Chandrashekhar Honrao 5,  Xiaoyu Ma 5,  Jason J Guo 5 6,  James M Berger 7,  Kim Lewis 8
Affiliations

Affiliations

  • 1 Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA.
  • 2 Department of Biomolecular Innovation, Institute for Biomedical Sciences, Shinshu University, Nagano, Japan.
  • 3 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 4 Bruker Biospin Corporation, Billerica, MA, USA.
  • 5 Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
  • 6 Barnett Institute for Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
  • 7 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jmberger@jhmi.edu.
  • 8 Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA. k.lewis@northeastern.edu.
  • # Contributed equally.
PMID: 35996001 DOI: 10.1038/s41589-022-01102-7
Abstract

The antimicrobial resistance crisis requires the introduction of novel Antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of Antibiotics. Here we show that a novel antimicrobial from Photorhabdus noenieputensis, which we named evybactin, is a potent and selective Antibiotic acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Given the conserved nature of DNA gyrase, the observed selectivity against M. tuberculosis is puzzling. We found that evybactin is smuggled into the cell by a promiscuous transporter of hydrophilic compounds, BacA. Evybactin is the first, but likely not the only, antimicrobial compound found to employ this unusual mechanism of selectivity.

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