The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation

Alessandra Crusco, Rafael Alves Baptista, Sumana Bhowmick, Manfred Beckmann, Luis Mur, Andrew D. Westwell, Karl Hoffmann

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1 Citation (Scopus)
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Abstract

A library of 14 minimally cytotoxic diterpenoid-like compounds (CC 50 > 70 μM on HepG2 human liver cells) was screened against Mycobacterium smegmatis, Staphylococcus aureus, and Escherichia coli to determine antimicrobial activity. Some compounds with a phenethyl alcohol (PE) core substituted with a β-cyclocitral derivative demonstrated anti-mycobacterial activity, with the most active being compound 1 (MIC = 23.4 mg/L, IC 50 = 0.6 mg/L). Lower activity was exhibited against S. aureus, while no activity was displayed against E. coli. Low cytotoxicity was re-confirmed on HepG2 cells and additionally on RAW 264.7 murine macrophages (SI for both cell lines > 38). The sub-lethal (IC 50 at 6 h) effect of compound 1 on M. smegmatis was examined through untargeted metabolomics and compared to untreated bacteria and bacteria treated with sub-lethal (IC 50 at 6 h) concentrations of the antituberculosis drugs ethambutol, isoniazid, kanamycin, and streptomycin. The study revealed that compound 1 acts differently from the reference antibiotics and that it significantly affects amino acid, nitrogen, nucleotides and folate-dependent one-carbon metabolism of M. smegmatis, giving some insights about the mode of action of this molecule. A future medicinal chemistry optimization of this new anti-mycobacterial core could lead to more potent molecules.

Original languageEnglish
Article number1444
JournalFrontiers in Microbiology
Volume10
Issue numberJUN
DOIs
Publication statusPublished - 25 Jun 2019

Keywords

  • terpenoids
  • diterpenoids
  • mycobacteria
  • tuberculosis
  • mycobacterium smegmatis
  • untargeted metabolomics
  • Tuberculosis
  • Terpenoids
  • Mycobacteria
  • Mycobacterium smegmatis
  • Diterpenoids
  • Untargeted metabolomics

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