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Structure paper

TitleSynthetic group A streptogramin antibiotics that overcome Vat resistance.
Journal, issue, pagesNature, Vol. 586, Issue 7827, Page 145-150, Year 2020
Publish dateSep 23, 2020
AuthorsQi Li / Jenna Pellegrino / D John Lee / Arthur A Tran / Hector A Chaires / Ruoxi Wang / Jesslyn E Park / Kaijie Ji / David Chow / Na Zhang / Axel F Brilot / Justin T Biel / Gydo van Zundert / Kenneth Borrelli / Dean Shinabarger / Cindy Wolfe / Beverly Murray / Matthew P Jacobson / Estelle Mühle / Olivier Chesneau / James S Fraser / Ian B Seiple /
PubMed AbstractNatural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance ...Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins, potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed. Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.
External linksNature / PubMed:32968273 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.5 - 3.05 Å
Structure data

20296

6pc5

EMDB-20296, PDB-6pc5:
E. coli 50S ribosome bound to compounds 46 and VS1
Method: EM (single particle) / Resolution: 2.7 Å

20297

6pc6

EMDB-20297, PDB-6pc6:
E. coli 50S ribosome bound to compound 47
Method: EM (single particle) / Resolution: 2.5 Å

20298

6pc7

EMDB-20298, PDB-6pc7:
E. coli 50S ribosome bound to compound 46
Method: EM (single particle) / Resolution: 2.5 Å

20299

6pc8

EMDB-20299, PDB-6pc8:
E. coli 50S ribosome bound to compound 40q
Method: EM (single particle) / Resolution: 2.9 Å

20300

6pch

EMDB-20300, PDB-6pch:
E. coli 50S ribosome bound to compound 21
Method: EM (single particle) / Resolution: 2.9 Å

20304

6pcq

EMDB-20304, PDB-6pcq:
E. coli 50S ribosome bound to VM2
Method: EM (single particle) / Resolution: 2.6 Å

20305

6pcr

EMDB-20305, PDB-6pcr:
E. coli 50S ribosome bound to compound 40o
Method: EM (single particle) / Resolution: 2.5 Å

20306

6pcs

EMDB-20306, PDB-6pcs:
E. coli 50S ribosome bound to compound 40e
Method: EM (single particle) / Resolution: 2.8 Å

20307

6pct

EMDB-20307, PDB-6pct:
E. coli 50S ribosome bound to compound 41q
Method: EM (single particle) / Resolution: 2.8 Å

21969

6wyv

EMDB-21969, PDB-6wyv:
E. coli 50S ribosome bound to compounds 47 and VS1
Method: EM (single particle) / Resolution: 2.75 Å

PDB-6x3c:
Crystal structure of streptogramin A acetyltransferase VatA from Staphylococcus aureus in complex with streptogramin analog F1037 (47)
Method: X-RAY DIFFRACTION / Resolution: 3.05 Å

PDB-6x3j:
Crystal structure of streptogramin A acetyltransferase VatA from Staphylococcus aureus in complex with streptogramin analog F0224 (46)
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

ChemComp-O7V:
(2R)-2-[(3S,4R,5E,10E,12E,14S,16R,26aR)-16-fluoro-14-hydroxy-4,12-dimethyl-1,7,22-trioxo-4,7,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosin-3-yl]propyl isoquinolin-3-ylcarbamate

ChemComp-O7S:
(3R,4R,5E,10E,12E,14S,16R,26aR)-16-fluoro-14-hydroxy-12-methyl-3-(propan-2-yl)-4-(prop-2-en-1-yl)-3,4,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,7H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,22-trione

ChemComp-O7Y:
(2R)-2-[(3S,4R,5E,10E,12E,14S,26aR)-14-hydroxy-4,12-dimethyl-1,7,16,22-tetraoxo-4,7,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosin-3-yl]propyl isoquinolin-3-ylcarbamate

ChemComp-O8D:
(3R,4R,5E,10E,12E,14S,26aR)-14-hydroxy-12-methyl-3-(propan-2-yl)-4-(prop-2-en-1-yl)-8,9,14,15,24,25,26,26a-octahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone

ChemComp-O8J:
(3R,4R,5E,10E,12E,14S,26aR)-14-hydroxy-4,12-dimethyl-3-(propan-2-yl)-8,9,14,15,24,25,26,26a-octahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone

ChemComp-O8P:
(2R)-2-[(3S,4R,5E,10E,12E,14S,26aR)-14-hydroxy-4,12-dimethyl-1,7,16,22-tetraoxo-4,7,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosin-3-yl]propyl (2-bromopyridin-4-yl)carbamate

ChemComp-O8S:
(2R)-2-[(3S,4R,5E,10E,12E,14S,26aR)-14-hydroxy-4,12-dimethyl-1,7,16,22-tetraoxo-4,7,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosin-3-yl]propyl [4-(trifluoromethyl)phenyl]carbamate

ChemComp-O8V:
(2S)-2-[(3S,4R,5E,10E,12E,14S,26aR)-14-hydroxy-4,12-dimethyl-1,7,16,22-tetraoxo-4,7,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,3H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosin-3-yl]propyl isoquinolin-3-ylcarbamate

ChemComp-SXA:
THIOACETIC ACID S-{2-[3-(2-HYDROXY-3,3-DIMETHYL-4-PHOSPHONOOXY-BUTYRYLAMINO)-PROPIONYLAMINO]-ETHYL} ESTER

ChemComp-PO4:
PHOSPHATE ION / Phosphate

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-CL:
Unknown entry / Chloride

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • escherichia coli (E. coli)
  • streptomyces virginiae (bacteria)
  • staphylococcus aureus (bacteria)
KeywordsRIBOSOME / E. coli ribosome / streptogramin A analog / antibiotics / TRANSFERASE / Acetyltransferase

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