Roles of the Sodium-Translocating NADH:Quinone Oxidoreductase (Na+-NQR) on Vibrio cholerae Metabolism, Motility and Osmotic Stress Resistance

Minato, Yusuke; Fassio, Sara R.; Kirkwood, Jay S.; Halang, Petra; Quinn, Matthew J.; Faulkner, Wyatt J.; Aagesen, Alisha M.; Steuber, Julia; Stevens, Jan F.; Häse, Claudia C.

doi:10.1371/journal.pone.0097083

Cited by 20 publications

(24 citation statements)

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“…Metabolism of cadaverine and succinate in the V. cholerae ⌬nqr strain. It was previously reported that cadaverine accumulates in the V. cholerae ⌬nqr strain (21), and cadA encoding the lysine decarboxylase was the most strongly upregulated gene in the nqr deletion strain in the transcriptomics study (21). This study also revealed very high expression of the lysine/cadaverine antiporter gene cadB.…”

Section: Resultssupporting

confidence: 62%

“…Previous transcriptomic and metabolomic studies of a V. cholerae ⌬nqr strain revealed changes in metabolic flow through the tricarboxylic acid (TCA) cycle, virulence factor production, and purine metabolism compared to those of the reference strain. In addition, lack of NQR resulted in increased accumulation of acetate in the medium (21). Our proteomebased results confirm downregulation of the oxidative branch of the TCA cycle observed previously (6,21) and reveal additional changes in the proteome of the V. cholerae ⌬nqr strain.…”

supporting

confidence: 86%

“…In addition, lack of NQR resulted in increased accumulation of acetate in the medium (21). Our proteomebased results confirm downregulation of the oxidative branch of the TCA cycle observed previously (6,21) and reveal additional changes in the proteome of the V. cholerae ⌬nqr strain. The lack of NQR strongly shifts nitrogen metabolism and triggers uptake and degradation of nucleosides.…”

supporting

confidence: 86%

“…What is the fate of acetate in the V. cholerae ⌬nqr strain? Excretion and reutilization of acetate (the so-called acetate switch) first described for Escherichia coli (25) were previously observed in the V. cholerae reference strain studied here (6,21). The authors also demonstrated that the V. cholerae ⌬nqr strain exhibited increased acetate production compared to the reference strain during growth on mixed amino acids at 30°C and concluded that in the absence of NQR, the acetate switch is broken (6).…”

Section: Resultsmentioning

confidence: 51%

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Metabolic Reprogramming of Vibrio cholerae Impaired in Respiratory NADH Oxidation Is Accompanied by Increased Copper Sensitivity

et al. 2018

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The electrogenic, sodium ion-translocating NADH:quinone oxidoreductase (NQR) from is frequent in pathogenic bacteria and a potential target for antibiotics. NQR couples the oxidation of NADH to the formation of a sodium motive force (SMF) and therefore drives important processes, such as flagellar rotation, substrate uptake, and energy-dissipating cation-proton antiport. We performed a quantitative proteome analysis of O395N1 compared to its variant lacking the NQR using minimal medium with glucose as the carbon source. We found 84 proteins (regulation factor of ≥2) to be changed in abundance. The loss of NQR resulted in a decrease in the abundance of enzymes of the oxidative branch of the tricarboxylic acid (TCA) cycle and an increase in abundance of virulence factors AcfC and TcpA. Most unexpected, the copper resistance proteins CopA, CopG, and CueR were decreased in the deletion strain. As a consequence, the mutant exhibited diminished resistance to copper compared to the reference strain, as confirmed in growth studies using either glucose or mixed amino acids as carbon sources. We propose that the observed adaptations of the deletion strain represent a coordinated response which counteracts a drop in transmembrane voltage that challenges in its different habitats. The importance of the central metabolism for bacterial virulence has raised interest in studying catabolic enzymes not present in the host, such as NQR, as putative targets for antibiotics. lacking the NQR, which is studied here, is a model to estimate the impact of specific NQR inhibitors on the phenotype of a pathogen. Our comparative proteomic study provides a framework to evaluate the chances of success of compounds directed against NQR with respect to their bacteriostatic or bactericidal action.

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Section: Resultssupporting

confidence: 62%

supporting

confidence: 86%

supporting

confidence: 86%

Section: Resultsmentioning

confidence: 51%

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Metabolic Reprogramming of Vibrio cholerae Impaired in Respiratory NADH Oxidation Is Accompanied by Increased Copper Sensitivity

et al. 2018

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“…In addition to this core NO 3 − reduction machinery, we identified two proteins that have not previously been implicated in NO 3 − respiration, including NqrF, a critical subunit of the Na+-translocating NADH:quinone dehydrogenase Nqr. In V. cholerae , Na + -Nqr has been reported to regulate bacterial motility, metabolism (30), resistance against heavy metals (31), and virulence (32–34). Deletion of Na + -Nqr in V. cholerae impaired membrane potential and delayed NO 3 − reduction to NO 2 − relative to the WT strain, suggesting that Na + -Nqr is required for maintenance of the ETC under NO 3 − respiratory conditions.…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of the fermentative and respiratory contributions supportingVibrio choleraehypoxic growth

Cendejas-Bueno

Sit

Waldor

et al. 2020

Preprint

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15Both fermentative and respiratory processes contribute to bacterial metabolic adaptations 16 to low oxygen tension (hypoxia). In the absence of O2 as a respiratory electron sink, many 17 bacteria utilize alternative electron acceptors such as nitrate (NO3 -). During canonical 18 NO3respiration, NO3is reduced in a stepwise manner to N2 by a dedicated set of 19 reductases. Vibrio cholerae, the etiological agent of cholera, only requires a single 20 periplasmic NO3reductase (NapA) to undergo NO3respiration, suggesting that the 21 pathogen possesses a non-canonical NO3respiratory chain. Here, we used 22 complementary transposon-based screens to identify genetic determinants of general 23 hypoxic growth and NO3respiration in V. cholerae. We found that while the V. cholerae 24 NO3respiratory chain is primarily composed of homologues of established NO3 -25 respiratory genes, it also includes components previously unlinked to this process, such 26 as the Na+-NADH dehydrogenase Nqr. The ethanol-generating enzyme AdhE was shown 27 to be the principal fermentative branch required during hypoxic growth in V. cholerae. 28Relative to single adhE or napA mutant strains, a V. cholerae strain lacking both genes 29 exhibited severely impaired hypoxic growth in vitro and in vivo. Our findings reveal the 30 genetic bases for interactions between disparate energy production pathways that support 31 pathogen fitness in shifting conditions. Such metabolic specializations in V. cholerae and 32 other pathogens are potential targets for antimicrobial interventions. 33 IMPORTANCE 34Bacteria reprogram their metabolism in environments with low oxygen levels (hypoxia). 35Typically, this occurs via regulation of two major, but largely independent, metabolic 36 pathways-fermentation and respiration. Here, we found that the diarrheal pathogen 37 Vibrio cholerae has a respiratory chain for NO3that consists largely of components found 38 in other NO3respiratory systems, but also contains several proteins not previously linked 39 to this process. Both AdhE-dependent fermentation and NO3respiration were required 40 for efficient pathogen growth in both laboratory conditions and in an animal infection 41 model. These observations provide genetic evidence for fermentative-respiratory 42 interactions and identify metabolic vulnerabilities that may be targetable for new 43 antimicrobial agents in V. cholerae and related pathogens. 44Respiration generates most of the energy produced in the cell, making it a vital 45 process to most organisms. Although the general mechanism of respiration is well-46 conserved, many bacteria employ specialized respiratory machineries for adaptation to 47 diverse environmental conditions. One such condition that bacteria frequently encounter 48 is the lack of oxygen, also known as hypoxia/anoxia. When oxygen is present, most 49 bacteria use molecular O2 as the terminal electron acceptor to drive aerobic respiration 50 and complete the electron transport chain (ETC). When O2 levels are insufficient to 51 support resp...

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Metabolomics of Vibrio cholerae

Minato

Kirkwood

Häse

2018

Methods in Molecular Biology

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Roles of the Sodium-Translocating NADH:Quinone Oxidoreductase (Na+-NQR) on Vibrio cholerae Metabolism, Motility and Osmotic Stress Resistance

Cited by 20 publications

References 24 publications

Metabolic Reprogramming of Vibrio cholerae Impaired in Respiratory NADH Oxidation Is Accompanied by Increased Copper Sensitivity

Metabolic Reprogramming of Vibrio cholerae Impaired in Respiratory NADH Oxidation Is Accompanied by Increased Copper Sensitivity

Genetic dissection of the fermentative and respiratory contributions supportingVibrio choleraehypoxic growth

Metabolomics of Vibrio cholerae

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