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)
Summary
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.
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