Small-molecule inhibitors of the NusB−NusE protein−protein interaction with antibiotic activity

Peter J. Cossar, Mohammed K. Abdel-Hamid, Cong Ma, Jennette A. Sakoff, Trieu N. Trinh, Christopher P. Gordon, Peter J. Lewis, Adam McCluskey

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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 ≤51 μg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB−NusE PPI as proposed.
Original languageEnglish
Pages (from-to)3839-3857
Number of pages19
JournalACS Omega
Volume2
Issue number7
DOIs
Publication statusPublished - 2017

Open Access - Access Right Statement

This is an open access article published under an ACS AuthorChoice License (https://pubs.acs.org/page/policy/authorchoice_termsofuse.html), which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Keywords

  • drug resistance in microorganisms
  • enterobacter
  • molecular dynamics
  • protein-protein interactions

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