Small-Molecule Inhibitors of the NusB-NusE Protein-Protein Interaction with Antibiotic Activity

ACS Omega
Peter J CossarAdam McCluskey

Abstract

The NusB-NusE protein-protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified N,N'-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 1 as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated 1 as a 20 μM potent inhibitor of NusB-NusE. Four focused compound libraries based on 1, comprising 34 compounds in total were designed, synthesized, and evaluated as NusB-NusE PPI inhibitors. Ten analogues displayed NusB-NusE PPI inhibition ≥50% at 25 μM concentration in vitro. In contrast to representative Gram-negative Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 μM. 2-((Z)-4-(((Z)-4-(4-((E)-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and ≤5...Continue Reading

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Citations

Jul 14, 2018·Medicinal Research Reviews·Peter J CossarAdam McCluskey
Oct 31, 2019·Transcription·Markus C Wahl, Ranjan Sen
Aug 31, 2021·RSC Chemical Biology·Rashi KahanAnna Barnard

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Methods Mentioned

BETA
NMR
X-ray
enzyme-linked immunosorbent assay
ELISA
PCR
SMA

Software Mentioned

MOE
CHARMM
- Dock
molecular operating environment ( MOE )
ELSIA
LigX
Accelrys Discovery Studio

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