Cell · 2023
Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhang Jidong, Lair Christine, Roubert Christine, Amaning Kwame, Barrio María Belén, Benedetti Yannick, Cui Zhicheng, Xing Zhongliang, Li Xiaojun, Franzblau Scott G, Baurin Nicolas, Bordon-Pallier Florence, Cantalloube Cathy, Sans Stephanie, Silve Sandra, Blanc Isabelle, Fraisse Laurent, Rak Alexey, Jenner Lasse B, Yusupova Gulnara, Yusupov Marat, Zhang Junjie, Kaneko Takushi, Yang T J, Fotouhi Nader, Nuermberger Eric, Tyagi Sandeep, Betoudji Fabrice, Upton Anna, Sacchettini James C, Lagrange Sophie
Аннотация
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.