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

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The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation. / Crusco, Alessandra; Alves Baptista, Rafael; Bhowmick, Sumana et al.

In: Frontiers in Microbiology, Vol. 10, No. JUN, 1444, 25.06.2019.

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

Harvard

Crusco, A, Alves Baptista, R, Bhowmick, S, Beckmann, M , Mur, L, Westwell, AD & Hoffmann, K 2019, 'The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation', Frontiers in Microbiology, vol. 10, no. JUN, 1444. https://doi.org/10.3389/fmicb.2019.01444

APA

Crusco, A., Alves Baptista, R., Bhowmick, S., Beckmann, M., Mur, L., Westwell, A. D., & Hoffmann, K. (2019). The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation. Frontiers in Microbiology, 10(JUN), [1444]. https://doi.org/10.3389/fmicb.2019.01444

Vancouver

Crusco A, Alves Baptista R, Bhowmick S, Beckmann M , Mur L, Westwell AD et al. The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation. Frontiers in Microbiology. 2019 Jun 25;10(JUN):1444. doi: 10.3389/fmicb.2019.01444

Author

Crusco, Alessandra ; Alves Baptista, Rafael ; Bhowmick, Sumana et al. / The anti-mycobacterial activity of a diterpenoid-like molecule operates through nitrogen and amino acid starvation. In: Frontiers in Microbiology. 2019 ; Vol. 10, No. JUN.

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 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.",

keywords = "terpenoids, diterpenoids, mycobacteria, tuberculosis, mycobacterium smegmatis, untargeted metabolomics, Tuberculosis, Terpenoids, Mycobacteria, Mycobacterium smegmatis, Diterpenoids, 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",

note = "Funding Information: We thank the Welsh Government, Life Sciences Research Network Wales scheme for financial support to AC and RB. IBERS receives strategic funding from the BBSRC. Publisher Copyright: {\textcopyright} 2007 - 2019 Frontiers Media S.A. All Rights Reserved.",

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",

number = "JUN",

}

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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

N1 - Funding Information: We thank the Welsh Government, Life Sciences Research Network Wales scheme for financial support to AC and RB. IBERS receives strategic funding from the BBSRC. Publisher Copyright: © 2007 - 2019 Frontiers Media S.A. All Rights Reserved.

PY - 2019/6/25

Y1 - 2019/6/25

N2 - 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.

AB - 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.

KW - terpenoids

KW - diterpenoids

KW - mycobacteria

KW - tuberculosis

KW - mycobacterium smegmatis

KW - untargeted metabolomics

KW - Tuberculosis

KW - Terpenoids

KW - Mycobacteria

KW - Mycobacterium smegmatis

KW - Diterpenoids

KW - Untargeted metabolomics