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

doi:10.3389/fmicb.2019.01444

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

Overview

Standard

The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation. / Crusco, Alessandra; Alves Baptista, Rafael; Bhowmick, Sumana; Beckmann, Manfred ; Mur, Luis; Westwell, Andrew D.; Hoffmann, Karl.

In: Frontiers in Microbiology, Vol. 10, 01444, 25.06.2019.

Research output: Contribution to journal › Article › peer-review

Bibtex - Download

@article{2d21c50c40284ad08df1d870457bcbe8,

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

abstract = "A library of 14 nontoxic 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 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 confirmed on HepG2 cells and newly derived for RAW 264.7 murine macrophages (SI > 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",

keywords = "terpenoids, diterpenoids, mycobacteria, tuberculosis, mycobacterium smegmatis, untargeted metabolomics",

author = "Alessandra Crusco and {Alves Baptista}, Rafael and Sumana Bhowmick and Manfred Beckmann and Luis Mur and Westwell, {Andrew D.} and Karl Hoffmann",

year = "2019",

month = jun,

day = "25",

doi = "10.3389/fmicb.2019.01444",

language = "English",

volume = "10",

journal = "Frontiers in Microbiology",

issn = "1664-302X",

publisher = "Frontiers Media",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation

AU - Crusco, Alessandra

AU - Alves Baptista, Rafael

AU - Bhowmick, Sumana

AU - Beckmann, Manfred

AU - Mur, Luis

AU - Westwell, Andrew D.

AU - Hoffmann, Karl

PY - 2019/6/25

Y1 - 2019/6/25

N2 - A library of 14 nontoxic 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 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 confirmed on HepG2 cells and newly derived for RAW 264.7 murine macrophages (SI > 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

AB - A library of 14 nontoxic 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 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 confirmed on HepG2 cells and newly derived for RAW 264.7 murine macrophages (SI > 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

KW - terpenoids

KW - diterpenoids

KW - mycobacteria

KW - tuberculosis

KW - mycobacterium smegmatis

KW - untargeted metabolomics

U2 - 10.3389/fmicb.2019.01444

DO - 10.3389/fmicb.2019.01444

M3 - Article

C2 - 31293560

VL - 10

JO - Frontiers in Microbiology