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TitleDiscovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.
Journal, issue, pagesCell, Vol. 186, Issue 5, Page 1013-1025.e24, Year 2023
Publish dateMar 2, 2023
AuthorsJidong 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 Yusupova / Marat Yusupov / Junjie Zhang / Takushi Kaneko / T J Yang / Nader Fotouhi / Eric Nuermberger / Sandeep Tyagi / Fabrice Betoudji / Anna Upton / James C Sacchettini / Sophie Lagrange /
PubMed AbstractThe 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 ...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.
External linksCell / PubMed:36827973 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.6 - 3.3 Å
Structure data

22865

7kgb

EMDB-22865, PDB-7kgb:
CryoEM structure of A2296-methylated Mycobacterium tuberculosis ribosome bound with SEQ-9
Method: EM (single particle) / Resolution: 2.7 Å

25100

7sfr

EMDB-25100, PDB-7sfr:
Unmethylated Mtb Ribosome 50S with SEQ-9
Method: EM (single particle) / Resolution: 2.6 Å

PDB-7azo:
70S thermus thermophilus ribosome with bound antibiotic lead SEQ-977
Method: X-RAY DIFFRACTION / Resolution: 3.3 Å

PDB-7azs:
70S thermus thermophilus ribosome with bound antibiotic lead SEQ-569
Method: X-RAY DIFFRACTION / Resolution: 3.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-OHX:
osmium (III) hexammine

ChemComp-K:
Unknown entry

ChemComp-SJE:
(2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-(((2R,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-((S)-1-(((2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-10-(((2S,3R,4R,6R)-3-hydroxy-4-(methoxyamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,5,7,9,11,13-hexamethyl-7-(((2-((2-nitrophenyl)sulfonamido)ethyl)carbamoyl)oxy)-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate

ChemComp-HOH:
WATER / Water

ChemComp-SJH:
(2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-(((2R,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-((S)-1-(((2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-10-(((2S,3R,6R,E)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,5,7,9,11,13-hexamethyl-7-(((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)carbamoyl)oxy)-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate

ChemComp-ZN:
Unknown entry

ChemComp-WDP:
Sequanamycin 9

Source
  • Mycobacterium tuberculosis H37Rv (bacteria)
  • mycobacterium tuberculosis (strain atcc 25618 / h37rv) (bacteria)
  • mycobacterium tuberculosis (bacteria)
  • thermus thermophilus hb8 (bacteria)
  • thermus thermophilus (strain hb8 / atcc 27634 / dsm 579) (bacteria)
  • escherichia coli (E. coli)
KeywordsRIBOSOME / translation / RNA / antibiotics / RIBOSOME/ANTIBIOTIC / Antibiotic / Methylation / Pathogen / RIBOSOME-ANTIBIOTIC complex / unmethylated / Mtb ribosome / drug discovery / SEQ-9 / Structural Genomics / TB Structural Genomics Consortium / TBSGC

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