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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

Authors :
Lici A. Schurig-Briccio
Robert B. Gennis
Andrea M. Lencina
Thierry Franza
Philippe Gaudu
Matthew J. Sullivan
Deepak S. Ipe
Glen C. Ulett
University of Illinois
University of Illinois System
MICrobiologie de l'ALImentation au Service de la Santé (MICALIS)
Institut National de la Recherche Agronomique (INRA)-AgroParisTech
Université Paris Saclay (COmUE)
Griffith University
United States National Institutes of Health [GM095600, HL16101]
Australia National Health and Medical Research Council [APP1146569, APP1146820]
Source :
mBio, Vol 9, Iss 4 (2018), mBio, mBio, American Society for Microbiology, 2018, 9 (4), ⟨10.1128/mBio.01034-18⟩, mBio 4 (9), . (2018), mBio, Vol 9, Iss 4, p e01034-18 (2018)
Publication Year :
2018
Publisher :
American Society for Microbiology, 2018.

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.&lt;br /&gt;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.

Details

Language :
English
ISSN :
21507511 and 21612129
Volume :
9
Issue :
4
Database :
OpenAIRE
Journal :
mBio
Accession number :
edsair.doi.dedup.....9c948ae14bfba2eec557f55e16215171
Full Text :
https://doi.org/10.1128/mBio.01034-18