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

Antibiotics
Zorik ChilingaryanAaron J Oakley

Abstract

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 whichEscherichia coliDnaG 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 using15N-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.

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Citations

Apr 5, 2019·Protein Science : a Publication of the Protein Society·Aaron J Oakley
Aug 15, 2018·Antibiotics·Stefan IlicBarak Akabayov
Jun 3, 2020·Chemistry : a European Journal·Meenakshi SinghBarak Akabayov
Jun 6, 2021·Protein Science : a Publication of the Protein Society·Piero R Bianco
Aug 31, 2021·RSC Chemical Biology·Rashi KahanAnna Barnard

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Methods Mentioned

BETA
X-ray
NMR
surface
PCR
chip

Software Mentioned

AutoDock Vina
TOPSPIN
CCPN
AutoDock Tools
GraphPad Prism
PROPKA

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