Discovery of two brominated oxindole alkaloids as staphylococcal DNA gyrase and pyruvate kinase inhibitors via inverse virtual screening

Ahmed M. Sayed, Hani A. Alhadrami, Seham S. El-Hawary, Rabab Mohammed, Hossam M. Hassan, Mostafa E. Rateb, Usama Ramadan Abdelmohsen, W. Bakeer*

*Corresponding author for this work

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3 Citations (Scopus)
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Abstract

In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.
Original languageEnglish
Article number293
Number of pages14
JournalMicroorganisms
Volume8
Issue number2
DOIs
Publication statusPublished - 20 Feb 2020

Keywords

  • MRSA
  • Trisindoline
  • Antibacterial
  • Antibiofilm
  • Inverse virtual screening
  • Gyrase-B
  • Pyruvate kinase
  • Marine natural products

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    Sayed, A. M., Alhadrami, H. A., El-Hawary, S. S., Mohammed, R., Hassan, H. M., Rateb, M. E., Ramadan Abdelmohsen, U., & Bakeer, W. (2020). Discovery of two brominated oxindole alkaloids as staphylococcal DNA gyrase and pyruvate kinase inhibitors via inverse virtual screening. Microorganisms, 8(2), [293]. https://doi.org/10.3390/microorganisms8020293