Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents
Jidong Zhang
(1)
,
Christine Lair
(2, 3)
,
Christine Roubert
(2, 3)
,
Kwame Amaning
(1)
,
Maria Belén Barrio
(3)
,
Yannick Benedetti
(1)
,
Zhicheng Cui
(4)
,
Zhongliang Xing
(4)
,
Xiaojun Li
(4)
,
Scott Franzblau
(5)
,
Nicolas Baurin
(1)
,
Florence Bordon-Pallier
(1)
,
Cathy Cantalloube
(1)
,
Stephanie Sans
(2, 3)
,
Sandra Silve
(2, 3)
,
Isabelle Blanc
(2, 3)
,
Laurent Fraisse
(2, 3)
,
Alexey Rak
(1)
,
Lasse Jenner
(6)
,
Gulnara Yusupova
(6)
,
Marat Yusupov
(6)
,
Junjie Zhang
(4)
,
Takushi Kaneko
(7)
,
T.J. Yang
(7)
,
Nader Fotouhi
(7)
,
Eric Nuermberger
(8)
,
Sandeep Tyagi
(8)
,
Fabrice Betoudji
(8)
,
Anna Upton
(2, 7)
,
James Sacchettini
(4)
,
Sophie Lagrange
(2, 3)
1
Sanofi [Vitry-sur-Seine]
2 Evotec ID [Lyon]
3 SANOFI Recherche
4 Texas A&M University [College Station]
5 UIC - University of Illinois [Chicago]
6 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
7 Global Alliance for TB Drug Development
8 Johns Hopkins University School of Medicine [Baltimore]
2 Evotec ID [Lyon]
3 SANOFI Recherche
4 Texas A&M University [College Station]
5 UIC - University of Illinois [Chicago]
6 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
7 Global Alliance for TB Drug Development
8 Johns Hopkins University School of Medicine [Baltimore]
Maria Belén Barrio
- Function : Author
- PersonId : 1262766
- IdHAL : belen-barrio
- ORCID : 0009-0005-7312-6127
Scott Franzblau
- Function : Author
- PersonId : 1268170
- ORCID : 0000-0002-8698-0243
Florence Bordon-Pallier
- Function : Author
- PersonId : 1268171
- ORCID : 0000-0003-2090-3744
T.J. Yang
- Function : Author
- PersonId : 1268172
- ORCID : 0000-0001-7392-6398
Anna Upton
- Function : Author
- PersonId : 1268173
- ORCID : 0000-0002-9522-1230
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.