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Open AccessArticle

Fragment-Based Discovery of Inhibitors of the Bacterial DnaG-SSB Interaction

1
Molecular Horizons and School of Chemistry, University of Wollongong, and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
2
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
3
Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
*
Author to whom correspondence should be addressed.
Antibiotics 2018, 7(1), 14; https://doi.org/10.3390/antibiotics7010014
Received: 15 January 2018 / Revised: 9 February 2018 / Accepted: 13 February 2018 / Published: 22 February 2018
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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. View Full-Text
Keywords: antibacterial agents; fragment-based screening; primase; protein–protein interactions; SSB antibacterial agents; fragment-based screening; primase; protein–protein interactions; SSB
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MDPI and ACS Style

Chilingaryan, Z.; Headey, S.J.; Lo, A.T.Y.; Xu, Z.-Q.; Otting, G.; Dixon, N.E.; Scanlon, M.J.; Oakley, A.J. Fragment-Based Discovery of Inhibitors of the Bacterial DnaG-SSB Interaction. Antibiotics 2018, 7, 14. https://doi.org/10.3390/antibiotics7010014

AMA Style

Chilingaryan Z, Headey SJ, Lo ATY, Xu Z-Q, Otting G, Dixon NE, Scanlon MJ, Oakley AJ. Fragment-Based Discovery of Inhibitors of the Bacterial DnaG-SSB Interaction. Antibiotics. 2018; 7(1):14. https://doi.org/10.3390/antibiotics7010014

Chicago/Turabian Style

Chilingaryan, Zorik; Headey, Stephen J.; Lo, Allen T.Y.; Xu, Zhi-Qiang; Otting, Gottfried; Dixon, Nicholas E.; Scanlon, Martin J.; Oakley, Aaron J. 2018. "Fragment-Based Discovery of Inhibitors of the Bacterial DnaG-SSB Interaction" Antibiotics 7, no. 1: 14. https://doi.org/10.3390/antibiotics7010014

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