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 language | English |
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Pages (from-to) | 3839-3857 |
Number of pages | 19 |
Journal | ACS Omega |
Volume | 2 |
Issue number | 7 |
DOIs | |
Publication status | Published - 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