Accumulation of heme biosynthetic intermediates contributes to the antibacterial action of the metalloid tellurite

Eduardo H. Morales; Camilo A. Pinto; Roberto Luraschi; Claudia M. Muñoz-Villagrán; Fabián A. Cornejo; Scott W. Simpkins; Justin Nelson; Felipe A. Arenas; Jeff S. Piotrowski; Chad L. Myers; Hirotada Mori; Claudio C. Vásquez

doi:10.1038/ncomms15320

Accumulation of heme biosynthetic intermediates contributes to the antibacterial action of the metalloid tellurite

Eduardo H. Morales, Camilo A. Pinto, Roberto Luraschi, Claudia M. Muñoz-Villagrán, Fabián A. Cornejo, Scott W. Simpkins, Justin Nelson, Felipe A. Arenas, Jeff S. Piotrowski, Chad L. Myers, Hirotada Mori, Claudio C. Vásquez

Computer Science and Engineering

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33 Scopus citations

Abstract

The metalloid tellurite is highly toxic to microorganisms. Several mechanisms of action have been proposed, including thiol depletion and generation of hydrogen peroxide and superoxide, but none of them can fully explain its toxicity. Here we use a combination of directed evolution and chemical and biochemical approaches to demonstrate that tellurite inhibits heme biosynthesis, leading to the accumulation of intermediates of this pathway and hydroxyl radical. Unexpectedly, the development of tellurite resistance is accompanied by increased susceptibility to hydrogen peroxide. Furthermore, we show that the heme precursor 5-Aminolevulinic acid, which is used as an antimicrobial agent in photodynamic therapy, potentiates tellurite toxicity. Our results define a mechanism of tellurite toxicity and warrant further research on the potential use of the combination of tellurite and 5-Aminolevulinic acid in antimicrobial therapy.

Original language	English (US)
Article number	15320
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15320
State	Published - 2017

Bibliographical note

Funding Information:
We thank Dr Juan Guerrero for advice and assistance in 1H NMR analysis. E.H.M. is supported by grant ‘Fondecyt Postdoctorado 3150004’, CONICYT, Chile. J.P.S. is supported by National Institutes of Health Grants 1R01HG005084. C.L.M. and J.N. are supported by National Institutes of Health Grants 1R01HG005084, 1R01GM104975 and R01HG005853 and National Science Foundation Grant DBI 0953881. S.W.S. is supported by an NSF Graduate Research Fellowship (00039202), an NIH Biotechnology training grant (T32GM008347). F.A.A. is supported by grant ‘Fondecyt de Iniciación en la Investigación 11140334’, CONICYT, Chile. H.M. is supported by grants JSPS Kakenhi 25250028, 16H02485 and MEXT Kakenhi 25108716, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. C.C.V. is supported by grants ‘Fondecyt Regular 1130362 and 1160051’, CONICYT, Chile.

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© The Author(s) 2017.

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Morales, E. H., Pinto, C. A., Luraschi, R., Muñoz-Villagrán, C. M., Cornejo, F. A., Simpkins, S. W., Nelson, J., Arenas, F. A., Piotrowski, J. S., Myers, C. L., Mori, H., & Vásquez, C. C. (2017). Accumulation of heme biosynthetic intermediates contributes to the antibacterial action of the metalloid tellurite. Nature communications, 8, Article 15320. https://doi.org/10.1038/ncomms15320

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title = "Accumulation of heme biosynthetic intermediates contributes to the antibacterial action of the metalloid tellurite",

abstract = "The metalloid tellurite is highly toxic to microorganisms. Several mechanisms of action have been proposed, including thiol depletion and generation of hydrogen peroxide and superoxide, but none of them can fully explain its toxicity. Here we use a combination of directed evolution and chemical and biochemical approaches to demonstrate that tellurite inhibits heme biosynthesis, leading to the accumulation of intermediates of this pathway and hydroxyl radical. Unexpectedly, the development of tellurite resistance is accompanied by increased susceptibility to hydrogen peroxide. Furthermore, we show that the heme precursor 5-Aminolevulinic acid, which is used as an antimicrobial agent in photodynamic therapy, potentiates tellurite toxicity. Our results define a mechanism of tellurite toxicity and warrant further research on the potential use of the combination of tellurite and 5-Aminolevulinic acid in antimicrobial therapy.",

author = "Morales, {Eduardo H.} and Pinto, {Camilo A.} and Roberto Luraschi and Mu{\~n}oz-Villagr{\'a}n, {Claudia M.} and Cornejo, {Fabi{\'a}n A.} and Simpkins, {Scott W.} and Justin Nelson and Arenas, {Felipe A.} and Piotrowski, {Jeff S.} and Myers, {Chad L.} and Hirotada Mori and V{\'a}squez, {Claudio C.}",

note = "Funding Information: We thank Dr Juan Guerrero for advice and assistance in 1H NMR analysis. E.H.M. is supported by grant {\textquoteleft}Fondecyt Postdoctorado 3150004{\textquoteright}, CONICYT, Chile. J.P.S. is supported by National Institutes of Health Grants 1R01HG005084. C.L.M. and J.N. are supported by National Institutes of Health Grants 1R01HG005084, 1R01GM104975 and R01HG005853 and National Science Foundation Grant DBI 0953881. S.W.S. is supported by an NSF Graduate Research Fellowship (00039202), an NIH Biotechnology training grant (T32GM008347). F.A.A. is supported by grant {\textquoteleft}Fondecyt de Iniciaci{\'o}n en la Investigaci{\'o}n 11140334{\textquoteright}, CONICYT, Chile. H.M. is supported by grants JSPS Kakenhi 25250028, 16H02485 and MEXT Kakenhi 25108716, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. C.C.V. is supported by grants {\textquoteleft}Fondecyt Regular 1130362 and 1160051{\textquoteright}, CONICYT, Chile. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

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AU - Pinto, Camilo A.

AU - Luraschi, Roberto

AU - Muñoz-Villagrán, Claudia M.

AU - Cornejo, Fabián A.

AU - Simpkins, Scott W.

AU - Nelson, Justin

AU - Arenas, Felipe A.

AU - Piotrowski, Jeff S.

AU - Myers, Chad L.

AU - Mori, Hirotada

AU - Vásquez, Claudio C.

N1 - Funding Information: We thank Dr Juan Guerrero for advice and assistance in 1H NMR analysis. E.H.M. is supported by grant ‘Fondecyt Postdoctorado 3150004’, CONICYT, Chile. J.P.S. is supported by National Institutes of Health Grants 1R01HG005084. C.L.M. and J.N. are supported by National Institutes of Health Grants 1R01HG005084, 1R01GM104975 and R01HG005853 and National Science Foundation Grant DBI 0953881. S.W.S. is supported by an NSF Graduate Research Fellowship (00039202), an NIH Biotechnology training grant (T32GM008347). F.A.A. is supported by grant ‘Fondecyt de Iniciación en la Investigación 11140334’, CONICYT, Chile. H.M. is supported by grants JSPS Kakenhi 25250028, 16H02485 and MEXT Kakenhi 25108716, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. C.C.V. is supported by grants ‘Fondecyt Regular 1130362 and 1160051’, CONICYT, Chile. Publisher Copyright: © The Author(s) 2017.

PY - 2017

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N2 - The metalloid tellurite is highly toxic to microorganisms. Several mechanisms of action have been proposed, including thiol depletion and generation of hydrogen peroxide and superoxide, but none of them can fully explain its toxicity. Here we use a combination of directed evolution and chemical and biochemical approaches to demonstrate that tellurite inhibits heme biosynthesis, leading to the accumulation of intermediates of this pathway and hydroxyl radical. Unexpectedly, the development of tellurite resistance is accompanied by increased susceptibility to hydrogen peroxide. Furthermore, we show that the heme precursor 5-Aminolevulinic acid, which is used as an antimicrobial agent in photodynamic therapy, potentiates tellurite toxicity. Our results define a mechanism of tellurite toxicity and warrant further research on the potential use of the combination of tellurite and 5-Aminolevulinic acid in antimicrobial therapy.

AB - The metalloid tellurite is highly toxic to microorganisms. Several mechanisms of action have been proposed, including thiol depletion and generation of hydrogen peroxide and superoxide, but none of them can fully explain its toxicity. Here we use a combination of directed evolution and chemical and biochemical approaches to demonstrate that tellurite inhibits heme biosynthesis, leading to the accumulation of intermediates of this pathway and hydroxyl radical. Unexpectedly, the development of tellurite resistance is accompanied by increased susceptibility to hydrogen peroxide. Furthermore, we show that the heme precursor 5-Aminolevulinic acid, which is used as an antimicrobial agent in photodynamic therapy, potentiates tellurite toxicity. Our results define a mechanism of tellurite toxicity and warrant further research on the potential use of the combination of tellurite and 5-Aminolevulinic acid in antimicrobial therapy.

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ER -

Accumulation of heme biosynthetic intermediates contributes to the antibacterial action of the metalloid tellurite

Abstract

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