7SFR

Unmethylated Mtb Ribosome 50S with SEQ-9

This is a non-PDB format compatible entry.

Summary for 7SFR

• Entry DOI: 10.2210/pdb7sfr/pdb
• EMDB information: 22865 25100
• Descriptor: 50S ribosomal protein L32, 50S ribosomal protein L3, 50S ribosomal protein L4, ... (54 entities in total)
• Functional Keywords: unmethylated, mtb ribosome, drug discovery, seq-9, structural genomics, tb structural genomics consortium, tbsgc, ribosome-antibiotic complex, ribosome/antibiotic
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 51
• Total formula weight: 2243571.27

Authors

Xing, Z.,Cui, Z.,Zhang, J.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2021-10-04, release date: 2022-10-12, Last modification date: 2024-06-05)

Primary citation

Zhang, J.,Lair, C.,Roubert, C.,Amaning, K.,Barrio, M.B.,Benedetti, Y.,Cui, Z.,Xing, Z.,Li, X.,Franzblau, S.G.,Baurin, N.,Bordon-Pallier, F.,Cantalloube, C.,Sans, S.,Silve, S.,Blanc, I.,Fraisse, L.,Rak, A.,Jenner, L.B.,Yusupova, G.,Yusupov, M.,Zhang, J.,Kaneko, T.,Yang, T.J.,Fotouhi, N.,Nuermberger, E.,Tyagi, S.,Betoudji, F.,Upton, A.,Sacchettini, J.C.,Lagrange, S.
Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.
Cell, 186:1013-, 2023

PubMed 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.

PubMed: 36827973
DOI: 10.1016/j.cell.2023.01.043

Experimental method

ELECTRON MICROSCOPY (2.6 Å)