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Fragment-based discovery of inhibitors of the bacterial DnaG-SSB interaction

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posted on 2024-11-16, 05:55 authored by Zorik Chilingaryan, Stephen J Headey, Allen Lo, Zhi-Qiang XuZhi-Qiang Xu, Gottfried Otting, Nicholas DixonNicholas Dixon, Martin J Scanlon, Aaron OakleyAaron Oakley
In bacteria, the DnaG primase is responsible for synthesis of short RNA primers used to initiate chain extension by replicative DNA polymerase(s) during chromosomal replication. Among the proteins with which Escherichia coli DnaG interacts is the single-stranded DNA-binding protein, SSB. The C-terminal hexapeptide motif of SSB (DDDIPF; SSB-Ct) is highly conserved and is known to engage in essential interactions with many proteins in nucleic acid metabolism, including primase. Here, fragment-based screening by saturation-transfer difference nuclear magnetic resonance (STD-NMR) and surface plasmon resonance assays identified inhibitors of the primase/SSB-Ct interaction. Hits were shown to bind to the SSB-Ct-binding site using 15N- 1H HSQC spectra. STD-NMR was used to demonstrate binding of one hit to other SSB-Ct binding partners, confirming the possibility of simultaneous inhibition of multiple protein/SSB interactions. The fragment molecules represent promising scaffolds on which to build to discover new antibacterial compounds.

Funding

Targeting lagging strand DNA replication in model and pathogenic bacteria

National Health and Medical Research Council

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Distributed facility for fragment based drug discovery

Australian Research Council

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History

Citation

Chilingaryan, Z., Headey, S. J., Lo, A. T. Y., Xu, Z., Otting, G., Dixon, N. E., Scanlon, M. J. & Oakley, A. J. (2018). Fragment-based discovery of inhibitors of the bacterial DnaG-SSB interaction. Antibiotics, 7 (1), 14-1-14-12.

Journal title

Antibiotics

Volume

7

Issue

1

Pagination

1-12

Language

English

RIS ID

123718

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