8QQI
E.coli DNA gyrase in complex with 217 bp substrate DNA and LEI-800
Summary for 8QQI
| Entry DOI | 10.2210/pdb8qqi/pdb |
| EMDB information | 18592 |
| Descriptor | DNA gyrase subunit A, DNA gyrase subunit B, Mu217 chain E, ... (6 entities in total) |
| Functional Keywords | topoisomerase, gyrase, allosteric inhibitor, antibiotic, dna binding protein |
| Biological source | Escherichia coli More |
| Total number of polymer chains | 6 |
| Total formula weight | 313843.23 |
| Authors | Ghilarov, D.,Martin, N.I.,van der Stelt, M. (deposition date: 2023-10-04, release date: 2024-06-19, Last modification date: 2024-09-18) |
| Primary citation | Bakker, A.T.,Kotsogianni, I.,Avalos, M.,Punt, J.M.,Liu, B.,Piermarini, D.,Gagestein, B.,Slingerland, C.J.,Zhang, L.,Willemse, J.J.,Ghimire, L.B.,van den Berg, R.J.H.B.N.,Janssen, A.P.A.,Ottenhoff, T.H.M.,van Boeckel, C.A.A.,van Wezel, G.P.,Ghilarov, D.,Martin, N.I.,van der Stelt, M. Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria. Nat.Chem., 16:1462-1472, 2024 Cited by PubMed Abstract: Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli. Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase-LEI-800-DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones. PubMed: 38898213DOI: 10.1038/s41557-024-01516-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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