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Journal Articles Cell Year : 2023

Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents

Jidong Zhang
  • Function : Author
Christine Lair
  • Function : Author
Christine Roubert
  • Function : Author
Kwame Amaning
  • Function : Author
María Belén Barrio
  • Function : Author
Yannick Benedetti
  • Function : Author
Zhicheng Cui
  • Function : Author
Zhongliang Xing
  • Function : Author
Xiaojun Li
  • Function : Author
Scott Franzblau
Nicolas Baurin
  • Function : Author
Florence Bordon-Pallier
Cathy Cantalloube
  • Function : Author
Stephanie Sans
  • Function : Author
Sandra Silve
  • Function : Author
Isabelle Blanc
  • Function : Author
Laurent Fraisse
  • Function : Author
Alexey Rak
  • Function : Author
Lasse Jenner
  • Function : Author
Marat Yusupov
  • Function : Author
Junjie Zhang
  • Function : Author
Takushi Kaneko
  • Function : Author
T.J. Yang
Nader Fotouhi
  • Function : Author
Eric Nuermberger
  • Function : Author
Sandeep Tyagi
  • Function : Author
Fabrice Betoudji
  • Function : Author
Anna Upton
James Sacchettini
  • Function : Author
Sophie Lagrange
  • Function : Author

Abstract

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.
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Dates and versions

hal-04266217 , version 1 (21-11-2023)

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Jidong Zhang, Christine Lair, Christine Roubert, Kwame Amaning, María Belén Barrio, et al.. Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents. Cell, 2023, 186 (5), pp.1013-1025.e24. ⟨10.1016/j.cell.2023.01.043⟩. ⟨hal-04266217⟩
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