Abstract

A library of 14 minimally cytotoxic diterpenoid-like compounds (CC50 > 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, IC50 = 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 (IC50 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 (IC50 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.

Highlights

  • Tuberculosis (TB), a highly infectious disease caused by the Mycobacterium tuberculosis (MTB), is included amongst the top 10 causes of human mortality according to the World Health Organization (World Health Organization [WHO], 2018)

  • In contrast to M. smegmatis, low to no activity was found for S. aureus and E. coli suggesting some degree of diterpenoid selectivity

  • To investigate potential antimicrobial activities of the previously synthesized diterpenoids (Crusco et al, 2018), a total of 14 related compounds were analyzed for their physicochemical properties and screened against S. aureus, E. coli and M. smegmatis (Table 1)

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Summary

Introduction

Tuberculosis (TB), a highly infectious disease caused by the Mycobacterium tuberculosis (MTB), is included amongst the top 10 causes of human mortality according to the World Health Organization (World Health Organization [WHO], 2018). A library of minimally cytotoxic diterpenoidlike compounds (CC50 > 70 μM on HepG2 human liver cells), previously synthesized and tested for anthelmintic activity (Crusco et al, 2018), was screened against Mycobacterium smegmatis.

Results
Conclusion

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