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Title | Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin. |
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Journal, issue, pages | Nat Catal, Vol. 6, Issue 1, Page 52-67, Year 2023 |
Publish date | Jan 23, 2023 |
Authors | Elizabeth Michalczyk / Kay Hommernick / Iraj Behroz / Marcel Kulike / Zuzanna Pakosz-Stępień / Lukasz Mazurek / Maria Seidel / Maria Kunert / Karine Santos / Holger von Moeller / Bernhard Loll / John B Weston / Andi Mainz / Jonathan G Heddle / Roderich D Süssmuth / Dmitry Ghilarov / |
PubMed Abstract | The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action is ...The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action is poorly understood. We determined a 2.6 Å resolution cryoelectron microscopy structure of a ternary complex between topoisomerase DNA gyrase, a 217 bp double-stranded DNA fragment and albicidin. Albicidin employs a dual binding mechanism where one end of the molecule obstructs the crucial gyrase dimer interface, while the other intercalates between the fragments of cleaved DNA substrate. Thus, albicidin efficiently locks DNA gyrase, preventing it from religating DNA and completing its catalytic cycle. Two additional structures of this trapped state were determined using synthetic albicidin analogues that demonstrate improved solubility, and activity against a range of gyrase variants and topoisomerase IV. The extraordinary promiscuity of the DNA-intercalating region of albicidins and their excellent performance against fluoroquinolone-resistant bacteria holds great promise for the development of last-resort antibiotics. |
External links | Nat Catal / PubMed:36741192 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.06 - 3.3 Å |
Structure data | EMDB-14570, PDB-7z9c: EMDB-14572, PDB-7z9g: EMDB-14573, PDB-7z9k: EMDB-14574, PDB-7z9m: |
Chemicals | ChemComp-MG: ChemComp-BWH: ChemComp-HOH: ChemComp-IM0: ChemComp-IL1: |
Source |
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Keywords | ISOMERASE / type II topoisomerase / antibiotic / albicidin / DNA gyrase |