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TitleDual site targeting of the bacterial 70S ribosome by tetracyclines.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateMay 19, 2026
AuthorsSwapnil C Devarkar / Ivan B Lomakin / Jimin Wang / Ayman Grada / Christopher G Bunick /
PubMed AbstractThe tetracycline class of antibiotics is widely used for treating bacterial diseases including Lyme disease, anthrax, acne vulgaris, and pneumonia. Using a series of high-resolution cryo-electron ...The tetracycline class of antibiotics is widely used for treating bacterial diseases including Lyme disease, anthrax, acne vulgaris, and pneumonia. Using a series of high-resolution cryo-electron microscopy (cryo-EM) structures, we show that tetracyclines can simultaneously target the mRNA decoding center in the 30S subunit and the nascent peptide exit tunnel (NPET) in the 50S subunit of the bacterial ribosome. Among the tested tetracyclines, Doxycycline was distinct in its ability to dimerize and bind the NPET at multiple locations. Structural comparison of Doxycycline, Minocycline, and Sarecycline bound to the Escherichia coli and Cutibacterium acnes 70S ribosome revealed species-specific differences affecting drug interaction and occupancy. Our results reveal a dual site mechanism of action for tetracyclines and provide a structural basis for rational design of narrow spectrum tetracyclines to overcome the rising threat of antibiotic resistance.
External linksNat Commun / PubMed:42156748 / PubMed Central
MethodsEM (single particle)
Resolution2.2 - 2.5 Å
Structure data

71667

9pih

EMDB-71667, PDB-9pih:
E. coli 70S ribosome bound to Doxycycline
Method: EM (single particle) / Resolution: 2.4 Å

71668

9pii

EMDB-71668, PDB-9pii:
E. coli 70S ribosome bound to Sarecycline
Method: EM (single particle) / Resolution: 2.4 Å

71669

9pij

EMDB-71669, PDB-9pij:
E. coli 70S ribosome bound to Minocycline
Method: EM (single particle) / Resolution: 2.2 Å

71682

9pj7

EMDB-71682, PDB-9pj7:
C. acnes 70S ribosome bound to Doxycycline
Method: EM (single particle) / Resolution: 2.4 Å

71683

9pj8

EMDB-71683, PDB-9pj8:
C. acnes 70S ribosome bound to Sarecycline
Method: EM (single particle) / Resolution: 2.5 Å

71684

9pj9

EMDB-71684, PDB-9pj9:
C. acnes 70S ribosome bound to Minocycline
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-K:
Unknown entry

ChemComp-DXT:
(4S,4AR,5S,5AR,6R,12AS)-4-(DIMETHYLAMINO)-3,5,10,12,12A-PENTAHYDROXY-6-METHYL-1,11-DIOXO-1,4,4A,5,5A,6,11,12A-OCTAHYDROTETRACENE-2-CARBOXAMIDE

ChemComp-HOH:
WATER

ChemComp-V7A:
Sarecycline / medication, antibiotic*YM

ChemComp-MIY:
(4S,4AS,5AR,12AS)-4,7-BIS(DIMETHYLAMINO)-3,10,12,12A-TETRAHYDROXY-1,11-DIOXO-1,4,4A,5,5A,6,11,12A-OCTAHYDROTETRACENE-2- / medication, antibiotic*YM

Source
  • escherichia coli (E. coli)
  • cutibacterium acnes (bacteria)
  • thermus thermophilus (bacteria)
KeywordsRIBOSOME / Tetracycline / bacterial ribosome / protein translation / Doxycycline / Antibiotic / Sarecycline / Minocycline / Cutibacterium acnes

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