Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target

ABSTRACT The opportunistic pathogen Streptococcus agalactiae is the major cause of meningitis and sepsis in a newborn’s first week, as well as a considerable cause of pneumonia, urinary tract infections, and sepsis in immunocompromised adults. This pathogen respires aerobically if heme and quinone a...

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Autores principales:	Andrea M. Lencina, Thierry Franza, Matthew J. Sullivan, Glen C. Ulett, Deepak S. Ipe, Philippe Gaudu, Robert B. Gennis, Lici A. Schurig-Briccio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	bacterial pathogenesis electron transport chain NADH dehydrogenase Streptococcus agalactiae drug discovery Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9ee87abcf36f44d8a3f82c3171f54252
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spelling	oai:doaj.org-article:9ee87abcf36f44d8a3f82c3171f542522021-11-15T16:00:14ZType 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target10.1128/mBio.01034-182150-7511https://doaj.org/article/9ee87abcf36f44d8a3f82c3171f542522018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01034-18https://doaj.org/toc/2150-7511ABSTRACT The opportunistic pathogen Streptococcus agalactiae is the major cause of meningitis and sepsis in a newborn’s first week, as well as a considerable cause of pneumonia, urinary tract infections, and sepsis in immunocompromised adults. This pathogen respires aerobically if heme and quinone are available in the environment, and a functional respiratory chain is required for full virulence. Remarkably, it is shown here that the entire respiratory chain of S. agalactiae consists of only two enzymes, a type 2 NADH dehydrogenase (NDH-2) and a cytochrome bd oxygen reductase. There are no respiratory dehydrogenases other than NDH-2 to feed electrons into the respiratory chain, and there is only one respiratory oxygen reductase to reduce oxygen to water. Although S. agalactiae grows well in vitro by fermentative metabolism, it is shown here that the absence of NDH-2 results in attenuated virulence, as observed by reduced colonization in heart and kidney in a mouse model of systemic infection. The lack of NDH-2 in mammalian mitochondria and its important role for virulence suggest this enzyme may be a potential drug target. For this reason, in this study, S. agalactiae NDH-2 was purified and biochemically characterized, and the isolated enzyme was used to screen for inhibitors from libraries of FDA-approved drugs. Zafirlukast was identified to successfully inhibit both NDH-2 activity and aerobic respiration in intact cells. This compound may be useful as a laboratory tool to inhibit respiration in S. agalactiae and, since it has few side effects, it might be considered a lead compound for therapeutics development. IMPORTANCE S. agalactiae is part of the human intestinal microbiota and is present in the vagina of ~30% of healthy women. Although a commensal, it is also the leading cause of septicemia and meningitis in neonates and immunocompromised adults. This organism can aerobically respire, but only using external sources of heme and quinone, required to have a functional electron transport chain. Although bacteria usually have a branched respiratory chain with multiple dehydrogenases and terminal oxygen reductases, here we establish that S. agalactiae utilizes only one type 2 NADH dehydrogenase (NDH-2) and one cytochrome bd oxygen reductase to perform respiration. NADH-dependent respiration plays a critical role in the pathogen in maintaining NADH/NAD+ redox balance in the cell, optimizing ATP production, and tolerating oxygen. In summary, we demonstrate the essential role of NDH-2 in respiration and its contribution to S. agalactiae virulence and propose it as a potential drug target.Andrea M. LencinaThierry FranzaMatthew J. SullivanGlen C. UlettDeepak S. IpePhilippe GauduRobert B. GennisLici A. Schurig-BriccioAmerican Society for Microbiologyarticlebacterial pathogenesiselectron transport chainNADH dehydrogenaseStreptococcus agalactiaedrug discoveryMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	bacterial pathogenesis electron transport chain NADH dehydrogenase Streptococcus agalactiae drug discovery Microbiology QR1-502
spellingShingle	bacterial pathogenesis electron transport chain NADH dehydrogenase Streptococcus agalactiae drug discovery Microbiology QR1-502 Andrea M. Lencina Thierry Franza Matthew J. Sullivan Glen C. Ulett Deepak S. Ipe Philippe Gaudu Robert B. Gennis Lici A. Schurig-Briccio Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target
description	ABSTRACT The opportunistic pathogen Streptococcus agalactiae is the major cause of meningitis and sepsis in a newborn’s first week, as well as a considerable cause of pneumonia, urinary tract infections, and sepsis in immunocompromised adults. This pathogen respires aerobically if heme and quinone are available in the environment, and a functional respiratory chain is required for full virulence. Remarkably, it is shown here that the entire respiratory chain of S. agalactiae consists of only two enzymes, a type 2 NADH dehydrogenase (NDH-2) and a cytochrome bd oxygen reductase. There are no respiratory dehydrogenases other than NDH-2 to feed electrons into the respiratory chain, and there is only one respiratory oxygen reductase to reduce oxygen to water. Although S. agalactiae grows well in vitro by fermentative metabolism, it is shown here that the absence of NDH-2 results in attenuated virulence, as observed by reduced colonization in heart and kidney in a mouse model of systemic infection. The lack of NDH-2 in mammalian mitochondria and its important role for virulence suggest this enzyme may be a potential drug target. For this reason, in this study, S. agalactiae NDH-2 was purified and biochemically characterized, and the isolated enzyme was used to screen for inhibitors from libraries of FDA-approved drugs. Zafirlukast was identified to successfully inhibit both NDH-2 activity and aerobic respiration in intact cells. This compound may be useful as a laboratory tool to inhibit respiration in S. agalactiae and, since it has few side effects, it might be considered a lead compound for therapeutics development. IMPORTANCE S. agalactiae is part of the human intestinal microbiota and is present in the vagina of ~30% of healthy women. Although a commensal, it is also the leading cause of septicemia and meningitis in neonates and immunocompromised adults. This organism can aerobically respire, but only using external sources of heme and quinone, required to have a functional electron transport chain. Although bacteria usually have a branched respiratory chain with multiple dehydrogenases and terminal oxygen reductases, here we establish that S. agalactiae utilizes only one type 2 NADH dehydrogenase (NDH-2) and one cytochrome bd oxygen reductase to perform respiration. NADH-dependent respiration plays a critical role in the pathogen in maintaining NADH/NAD+ redox balance in the cell, optimizing ATP production, and tolerating oxygen. In summary, we demonstrate the essential role of NDH-2 in respiration and its contribution to S. agalactiae virulence and propose it as a potential drug target.
format	article
author	Andrea M. Lencina Thierry Franza Matthew J. Sullivan Glen C. Ulett Deepak S. Ipe Philippe Gaudu Robert B. Gennis Lici A. Schurig-Briccio
author_facet	Andrea M. Lencina Thierry Franza Matthew J. Sullivan Glen C. Ulett Deepak S. Ipe Philippe Gaudu Robert B. Gennis Lici A. Schurig-Briccio
author_sort	Andrea M. Lencina
title	Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target
title_short	Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target
title_full	Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target
title_fullStr	Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target
title_full_unstemmed	Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target
title_sort	type 2 nadh dehydrogenase is the only point of entry for electrons into the <named-content content-type="genus-species">streptococcus agalactiae</named-content> respiratory chain and is a potential drug target
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/9ee87abcf36f44d8a3f82c3171f54252
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Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the <named-content content-type="genus-species">Streptococcus agalactiae</named-content> Respiratory Chain and Is a Potential Drug Target

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