nadA and nadB of Shigella flexneri 5a are antivirulence loci responsible for the synthesis of quinolinate, a small molecule inhibitor of Shigella pathogenicity

Prunier, Anne-Laure; Schuch, Raymond; Fernández, Reinaldo E.; Mumy, Karen L.; Köhler, Henrik; McCormick, Beth A.; Maurelli, Anthony T.

doi:10.1099/mic.0.2007/006916-0

Cited by 64 publications

(58 citation statements)

References 39 publications

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“…As mentioned above, neither of the two known biochemical pathways of Qa synthesis (from Asp or from Trp) is present in Streptococcus species, suggesting that Qa can either be produced by a third, yet unknown, pathway or, more likely, it can be scavenged from the host. The only known precedent for the latter was reported in some highly virulent isolates of Shigella with multiple mutations inactivating nadB and nadA, but not nadC, genes (34,35). In this study, we combined gene disruption/growth phenotype approaches to discern these two possibilities and elucidate the physiological role of NadC in group A streptococci.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in this pathogen, the loss of function by mutations and deletions of de novo nadB and nadA genes, along with the presence of nadC, was implicated in virulence (35). Moreover, quinolinate was demonstrated to be a strong inhibitor of Shigella virulence (34). Given a relatively low abundance of Qa (compared to Nm and Na) in the human body, the preservation of QaPRT function in Shigella and Streptococcus is more likely driven by its scavenging function rather than an actual contribution to NAD biogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Sorci¹,

Blaby²,

Rodionova³

et al. 2012

Journal of Bacteriology

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eThe essential coenzyme NAD plays important roles in metabolic reactions and cell regulation in all organisms. As such, NAD synthesis has been investigated as a source for novel antibacterial targets. Cross-species genomics-based reconstructions of NAD metabolism in group A streptococci (GAS), combined with focused experimental testing in Streptococcus pyogenes, led to a better understanding of NAD metabolism in the pathogen. The predicted niacin auxotrophy was experimentally verified, as well as the essential role of the nicotinamidase PncA in the utilization of nicotinamide (Nm). PncA is dispensable in the presence of nicotinate (Na), ruling it out as a viable antibacterial target. The function of the "orphan" NadC enzyme, which is uniquely present in all GAS species despite the absence of other genes of NAD de novo synthesis, was elucidated. Indeed, the quinolinate (Qa) phosphoribosyltransferase activity of NadC from S. pyogenes allows the organism to sustain growth when Qa is present as a sole pyridine precursor. Finally, the redundancy of functional upstream salvage pathways in GAS species narrows the choice of potential drug targets to the two indispensable downstream enzymes of NAD synthesis, nicotinate adenylyltransferase (NadD family) and NAD synthetase (NadE family). Biochemical characterization of NadD confirmed its functional role in S. pyogenes, and its potential as an antibacterial target was supported by inhibition studies with previously identified class I inhibitors of the NadD enzyme family. One of these inhibitors efficiently inhibited S. pyogenes NadD (sp.NadD) in vitro (50% inhibitory concentration [IC 50 ], 15 M), exhibiting a noncompetitive mechanism with a K i of 8 M.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Sorci¹,

Blaby²,

Rodionova³

et al. 2012

Journal of Bacteriology

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“…This finding is validated by previous literature confirming that quinolate inhibits invasion and cell-to-cell spread of Shigella flexneri 5a. Reintroduction of functional copies of nadA and nadB into this strain restored the ability to synthesize quinolate but also resulted in strong attenuation of virulence in this strain (35). Therefore, several of the additional auxotrophies identified for other vitamins such as folate and thiamin, as well as amino acids leucine, methionine, and tryptophan, may indicate further cases of antagonistic pleiotrophy.…”

Section: Discussionmentioning

confidence: 99%

Genome-scale metabolic reconstructions of multiple Escherichia coli strains highlight strain-specific adaptations to nutritional environments

Monk¹,

Charusanti

Aziz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

264

284

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Genome-scale models (GEMs) of metabolism were constructed for 55 fully sequenced Escherichia coli and Shigella strains. The GEMs enable a systems approach to characterizing the pan and core metabolic capabilities of the E. coli species. The majority of pan metabolic content was found to consist of alternate catabolic pathways for unique nutrient sources. The GEMs were then used to systematically analyze growth capabilities in more than 650 different growth-supporting environments. The results show that unique strain-specific metabolic capabilities correspond to pathotypes and environmental niches. Twelve of the GEMs were used to predict growth on six differentiating nutrients, and the predictions were found to agree with 80% of experimental outcomes. Additionally, GEMs were used to predict strain-specific auxotrophies. Twelve of the strains modeled were predicted to be auxotrophic for vitamins niacin (vitamin B 3 ), thiamin (vitamin B 1 ), or folate (vitamin B 9 ). Six of the strains modeled have lost biosynthetic pathways for essential amino acids methionine, tryptophan, or leucine. Genome-scale analysis of multiple strains of a species can thus be used to define the metabolic essence of a microbial species and delineate growth differences that shed light on the adaptation process to a particular microenvironment.systems biology | mathematical modeling | core and pan genome

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“…They typically lack many E. coli metabolic genes and the loss of some of these loci is pathoadaptive [127,128].…”

Section: Enteroinvasive E Coli and Shigellamentioning

confidence: 99%

Diarrheagenic Escherichia coli in sub-Saharan Africa: Status, Uncertainties and Necessities

Okeke

2009

J Infect Dev Ctries

121

103

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Diarrhea is a leading cause of illness and death, particularly in developing countries. Enteropathogenic Escherichia coli, enterotoxigenic E. coli (ETEC), enteroinvasive E. coli, enterohemorrhaghic E. coli (EHEC), enteroaggregative E. coli (EAEC) and diffusely adherent E. coli (DAEC) have been associated with diarrheal disease in different parts of Africa, particularly among young children, HIV-positive individuals, and visitors from abroad. Each of these E. coli pathotypes uses distinct mechanisms, which are only partially understood, to colonize infected hosts and produce diarrhea. All known diarrheagenic E. coli pathotypes have been reported from diverse locations within Africa but the true burden from these pathogens is unknown because very few studies seeking these organisms with discriminatory methodology have been performed. Recent reports implicate ETEC and EAEC in a considerable proportion of childhood and travellers' diarrheas and suggest that some sub-types of these categories may have greater epidemiological significance than others. The significant contribution of EHEC to bloody diarrhea and hemolytic uremic syndrome is underappreciated because diagnostic capacity for this pathotype is generally inferior to that for confounders such as Shigella and Entamoeba. Recent studies in Africa have revealed the worrisome emergence of antimicrobial resistance and high asymptomatic carriage rates for diarrheagenic E. coli but bacterial and host factors that predispose to disease, as well as non-human reservoirs, are largely unknown. Future diarrheal disease research needs to focus on broadening the repertoire of pathogens sought in epidemiological surveys to include multiple categories of diarrheagenic E. coli while building capacity to detect these pathogens in local reference laboratories.

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nadA and nadB of Shigella flexneri 5a are antivirulence loci responsible for the synthesis of quinolinate, a small molecule inhibitor of Shigella pathogenicity

Cited by 64 publications

References 39 publications

Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Genome-scale metabolic reconstructions of multiple Escherichia coli strains highlight strain-specific adaptations to nutritional environments

Diarrheagenic Escherichia coli in sub-Saharan Africa: Status, Uncertainties and Necessities

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