Identification and validation of small molecule modulators of the NusB-NusE interaction

摘要

Formation of highly possessive antitermination complexes is crucial for the efficient transcription of stable RNA in all bacteria. A key step in the formation of these complexes is the protein-protein interaction (PPI) between N-utilisation substances (Nus) B and E and thus this PPI offers a novel target for a new antibiotic class. A pharmacophore developed via a secondary structure epitope approach was utilised to perform an in silico screen of the mini-Maybridge library (56,000 compounds) which identified 25 hits of which five compounds were synthetically tractable leads. Here we report the synthesis of these five leads and their biological evaluation as potential inhibitors of the NusB-NusE PPI. Two chemically diverse scaffolds were identified to be low micro molar potent PPI inhibitors, with compound (4,6-bis(2′,4′,3.4 tetramethoxyphenyl))pyrimidine-2-sulphonamido-N-4-acetamide 1 and N,N′-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 3 exhibiting IC50 values of 6.1 μM and 19.8 μM, respectively. These inhibitors were also shown to be moderate inhibitors of Gram-positive Bacillus subtilis and Gram-negative Escherichia coli growth.