Discovery of Evybactin, a New Antibiotic Expected to be a Lead Compound for Future Tuberculosis Drugs
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Assistant Professor Yu Imai of Institute for Biomedical Sciences, Shinshu University has discovered a new antibiotic that specifically kills Mycobacterium tuberculosis from the Photorhabdus nematode symbionts at the Antimicrobial Discovery Center, Northeastern University, where he was studying under Distinguished Professor Kim Lewis.
Tuberculosis (TB) is still today a major threat, especially in developing countries, where 9.9 million people are infected annually and 1.5 million people die (World Health Organization, 2020). To prevent the emergence of drug-resistant strains, a cocktail of four antibiotics with different mechanisms of action, rifampicin, isoniazid, pyrazinamide, and ethambutol, is used for the treatment of TB, which require about 6 months. Among these antibiotics, rifampicin acts against a wide range of bacteria, and there were concerns that long-term use of this cocktail might affect the human flora and cause the emergence of drug-resistant mutants from non-target bacteria. Therefore, there was an urgent need to discover an antibiotic that is active only against Mycobacterium tuberculosis.
In this research, screening the antibiotics from Photorhabdus and Xenorhabdus nematode symbionts, and we succeeded in discovering a new antibiotic, Evybactin, from Photorhabdus noenieputensis that is active only against Mycobacterium tuberculosis. Evybactin is taken up into cells by the Mycobacterium tuberculosis’ BacA transporter, which involved in the uptake of hydrophilic molecules, and kills Mycobacterium tuberculosis by inhibiting the function of DNA gyrase, an essential enzyme for DNA replication in bacteria.
In Gram-negative bacteria such as Escherichia coli, it was found that evybactin is taken up into the cell via a homologue of the BacA transporter, SbmA transporter, and while pumped out of the cell by the action of a drug efflux pump, such as AcrAB-TolC etc.. This indicates that evybactin is "consequently" selective for Mycobacterium tuberculosis. (Figure)
Simple animal experiments have also shown that evybactin inhibits the growth of pathogenic bacteria in vivo in mice without losing its activity, and thus, it holds great promise as a lead compound for future tuberculosis drugs.
The results of the research were published in the scientific journal Nature Chemical Biology on August 23, 2022 at 0:00 (Japan Standard Time).
For more details of the research, please refer to the following:
Authors: Yu Imai, Glenn Hauk, Jeffrey Quigley, Libang Liang, Sangkeun Son, Meghan Ghiglieri, Michael F. Gates, Madeleine Morrissette, Negar Shahsavari, Samantha Niles, Donna Baldisseri, Chandrashekhar Honrao, Xiaoyu Ma, Jason J. Guo, James Berger, Kim Lewis
Title: Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis
Journal: Nature Chemical Biology (2022)
DOI: 10.1038/s41589-022-01102-7
