@article{f8291dc25bd84355a70eacb7d117dbe8,
title = "Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents",
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.",
keywords = "antibacterial, clarithromycin, drug discovery, emr37, erythromycin, macrolide, ribosome, sequanamycin, tuberculosis",
author = "Jidong Zhang and Christine Lair and Christine Roubert and Kwame Amaning and Barrio, {Mar{\'i}a Bel{\'e}n} and Yannick Benedetti and Zhicheng Cui and Zhongliang Xing and Xiaojun Li and Franzblau, {Scott G.} and Nicolas Baurin and Florence Bordon-Pallier and Cathy Cantalloube and Stephanie Sans and Sandra Silve and Isabelle Blanc and Laurent Fraisse and Alexey Rak and Jenner, {Lasse B.} and Gulnara Yusupova and Marat Yusupov and Junjie Zhang and Takushi Kaneko and Yang, {T. J.} and Nader Fotouhi and Eric Nuermberger and Sandeep Tyagi and Fabrice Betoudji and Anna Upton and Sacchettini, {James C.} and Sophie Lagrange",
note = "Funding Information: We thank M.C. Bergot and C. Lattemann (Sanofi Industrial affaire) for supplying sequanamycin; E. Bouley, B. Charnay, J. Mauvignant, and C. Lavie (Sanofi Integrated Drug Discovery Department) for the syntheses of sequanamycin derivatives; C. Perron (Sanofi anti-infective Research) for performing the in vivo study (short acute); Manisha Lotlikar Global Alliance for TB Drug Development and Khisi Mdluli Global Alliance for TB Drug Development for coordinating discussions for the drug combination studies; the Microscopy and Imaging Center at Texas A&M University for providing instrumentation for the initial screening of cryo-EM specimens; the Texas A&M High-Performance Research Computing Center for providing the computational resources for the data processing; and the cryo-EM regional data collection consortium for grant U24GM116787. We are grateful to members of and advisors to the TB Drug Accelerator Program. We thank Nadir Bessila for advice, discussions, and outstanding project management. Funding for this work was provided by the NIH TB Structural Genomics grant P01AI095208 (to Junjie Zhang and J.C.S.), the Welch Foundation grants A-1863 and A-0015 (to Junjie Zhang and J.C.S. respectively), and by Sanofi. We also acknowledge funding from the TB Drug Accelerator Program of the Bill and Melinda Gates Foundation. Jidong Zhang was co-leader of the program and directed the medicinal optimization program, and M.B.B. and C.L. were successive leaders of the biological program. C.R. C.L. M.B.B. S. Sans, and S. Silve designed and performed microbiological studies. Jidong Zhang, K.A. Y.B. and N.B. designed the sequanamycin derivatives, and Jidong Zhang and Y.B. supervised and realized the syntheses of sequanamycin derivatives. K.A. and N.B. built ligand-ribosome interaction model from T. thermophilus ribosome X-ray structures and performed molecular modeling studies. Z.C. Z.X. X.L. J.C.S. and Junjie Zhang carried out structural studies and analysis of the Mtb ribosome. X.L. and J.C.S. were responsible for the translation assays and analysis. F.B.-P. identified seqanamycin A from the Rh{\^o}ne-Poulenc archives, C.C. coordinated the DMPK studies, I.B. designed and realized in vivo studies (short acute and acute models), and L.F. and S.L. supervised the overall sequanamycin program. A.R. performed ribosome-ligand X-ray structure determination management and analysis in T. thermophilus. L.B.J. performed ribosome isolation and data collection and structure determination and model building in T. thermophilus. G.Y. performed complex formation and ribosome crystallization, and G.Y. and M.Y. designed ribosome X-ray structure determination strategy in T. thermophilus. Jidong Zhang, A.U. T.K. T.J.Y. N.F. E.N. S.T. and F.B. designed and performed the in vivo combination studies. S.G.F. performed in vivo study of chronic model. Jidong Zhang, J.Z. C.L. K.A. C.R. A.R. J.C.S. and S.L. wrote the paper. All authors discussed the results and commented on the manuscript. Jidong Zhang, K.A. Y.B. N.B. F.B.-P. C.C. and A.R. are employed by Sanofi R&D. C.L. C.R. S. Sans, S. Silve, I.B. and S.L. were employed by Sanofi R&D and now Evotec. M.B.B. was employed by Sanofi R&D and now Inrae, France. L.F. was employed by Sanofi R&D and now Drugs for Neglected Diseases initiative (DNDi), Switzerland. Funding Information: We thank M.C. Bergot and C. Lattemann (Sanofi Industrial affaire) for supplying sequanamycin; E. Bouley, B. Charnay, J. Mauvignant, and C. Lavie (Sanofi Integrated Drug Discovery Department) for the syntheses of sequanamycin derivatives; C. Perron (Sanofi anti-infective Research) for performing the in vivo study (short acute); Manisha Lotlikar Global Alliance for TB Drug Development and Khisi Mdluli Global Alliance for TB Drug Development for coordinating discussions for the drug combination studies; the Microscopy and Imaging Center at Texas A&M University for providing instrumentation for the initial screening of cryo-EM specimens; the Texas A&M High-Performance Research Computing Center for providing the computational resources for the data processing; and the cryo-EM regional data collection consortium for grant U24GM116787. We are grateful to members of and advisors to the TB Drug Accelerator Program. We thank Nadir Bessila for advice, discussions, and outstanding project management. Funding for this work was provided by the NIH TB Structural Genomics grant P01AI095208 (to Junjie Zhang and J.C.S.), the Welch Foundation grants A-1863 and A-0015 (to Junjie Zhang and J.C.S., respectively), and by Sanofi . We also acknowledge funding from the TB Drug Accelerator Program of the Bill and Melinda Gates Foundation . Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = mar,
day = "2",
doi = "10.1016/j.cell.2023.01.043",
language = "English (US)",
volume = "186",
pages = "1013--1025.e24",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}