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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1013-1025.e24
Issue number5
StatePublished - Mar 2 2023


  • antibacterial
  • clarithromycin
  • drug discovery
  • emr37
  • erythromycin
  • macrolide
  • ribosome
  • sequanamycin
  • tuberculosis

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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