Oral Presentation RACI Biomolecular Division Conference 2013

The β-sliding clamp is an accessory protein to the Escherichia coli DNA polymerase III holoenzyme and plays an essential role in bacterial chromosomal replication.¹  It is conserved across a wide range of bacterial strains but is structurally distinct from its analogous human counterpart.²  The β-sliding clamp is thus an excellent target for the development of novel antibacterial agents, which have the potential to be both selective and broad spectrum. The β-sliding clamp plays several ancillary roles in DNA replication and repair, and inhibition would result in the disruption of multiple essential cellular processes minimising the likelihood of target-based drug resistance.³

Fragment-based screening (FBS) employing X-ray crystallography in combination with fluorescence polarisation assays is being used in our laboratories to identify binders of the β-sliding clamp. One of the hits, a tetrahydrocarbazole (Figure 1) with moderate binding affinity (K_D = 166 µM), was selected as the lead scaffold for an SAR study aimed at increasing affinity. Using the X-ray crystallography data of this fragment (and others) bound to the β-sliding clamp we’ve prepared and studied a range of first generation derivatives (Figure 1). The SAR information coupled with X-ray data has led us to target a second generation of derivatives carrying substitutions at the indole nitrogen.