AUTHOR=Crusco Alessandra , Baptista Rafael , Bhowmick Sumana , Beckmann Manfred , Mur Luis A. J. , Westwell Andrew D. , Hoffmann Karl F. 

TITLE=The Anti-mycobacterial Activity of a Diterpenoid-Like Molecule Operates Through Nitrogen and Amino Acid Starvation

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.01444

DOI=10.3389/fmicb.2019.01444

ISSN=1664-302X

ABSTRACT=<p>A library of 14 minimally cytotoxic diterpenoid-like compounds (CC<sub>50</sub> &gt; 70 μM on HepG2 human liver cells) was screened against <italic>Mycobacterium smegmatis</italic>, <italic>Staphylococcus aureus</italic>, and <italic>Escherichia coli</italic> 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 <bold>1</bold> (MIC = 23.4 mg/L, IC<sub>50</sub> = 0.6 mg/L). Lower activity was exhibited against <italic>S. aureus</italic>, while no activity was displayed against <italic>E. coli.</italic> Low cytotoxicity was re-confirmed on HepG2 cells and additionally on RAW 264.7 murine macrophages (SI for both cell lines &gt; 38). The sub-lethal (IC<sub>50</sub> at 6 h) effect of compound <bold>1</bold> on <italic>M. smegmatis</italic> was examined through untargeted metabolomics and compared to untreated bacteria and bacteria treated with sub-lethal (IC<sub>50</sub> at 6 h) concentrations of the antituberculosis drugs ethambutol, isoniazid, kanamycin, and streptomycin. The study revealed that compound <bold>1</bold> acts differently from the reference antibiotics and that it significantly affects amino acid, nitrogen, nucleotides and folate-dependent one-carbon metabolism of <italic>M. smegmatis</italic>, 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.</p>