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Fructose-asparagine is a primary nutrient during growth of Salmonella in the inflamed intestine.

ABSTRACT: Salmonella enterica serovar Typhimurium (Salmonella) is one of the most significant food-borne pathogens affecting both humans and agriculture. We have determined that Salmonella encodes an uptake and utilization pathway specific for a novel nutrient, fructose-asparagine (F-Asn), which is essential for Salmonella fitness in the inflamed intestine (modeled using germ-free, streptomycin-treated, ex-germ-free with human microbiota, and IL10-/- mice). The locus encoding F-Asn utilization, fra, provides an advantage only if Salmonella can initiate inflammation and use tetrathionate as a terminal electron acceptor for anaerobic respiration (the fra phenotype is lost in Salmonella SPI1- SPI2- or ttrA mutants, respectively). The severe fitness defect of a Salmonella fra mutant suggests that F-Asn is the primary nutrient utilized by Salmonella in the inflamed intestine and that this system provides a valuable target for novel therapies.

SUBMITTER: Ali MM

PROVIDER: S-EPMC4072780 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Fructose-asparagine is a primary nutrient during growth of Salmonella in the inflamed intestine.

Ali Mohamed M MM Newsom David L DL González Juan F JF Sabag-Daigle Anice A Stahl Christopher C Steidley Brandi B Dubena Judith J Dyszel Jessica L JL Smith Jenee N JN Dieye Yakhya Y Arsenescu Razvan R Boyaka Prosper N PN Krakowka Steven S Romeo Tony T Behrman Edward J EJ White Peter P Ahmer Brian M M BM

PLoS pathogens 20140626 6

Salmonella enterica serovar Typhimurium (Salmonella) is one of the most significant food-borne pathogens affecting both humans and agriculture. We have determined that Salmonella encodes an uptake and utilization pathway specific for a novel nutrient, fructose-asparagine (F-Asn), which is essential for Salmonella fitness in the inflamed intestine (modeled using germ-free, streptomycin-treated, ex-germ-free with human microbiota, and IL10-/- mice). The locus encoding F-Asn utilization, fra, provi ...[more]

PMID: 24967579

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Project description:Salmonella enterica serovar Typhimurium is the only organism demonstrated to utilize fructose-asparagine (F-Asn) as a source of carbon and nitrogen. In this report, we first used a bioinformatics approach to identify other microorganisms that encode homologs of the Salmonella F-Asn utilization enzymes FraB (deglycase), FraD (kinase), and FraE (asparaginase). These candidate organisms were then tested with up to four different methods to confirm their ability to utilize F-Asn. The easiest and most broadly applicable method utilized a biological toxicity assay, which is based on the observation that F-Asn is toxic to a Salmonella fraB mutant. Candidate organisms were grown in a rich medium containing F-Asn, and depletion of F-Asn from the medium was inferred by the growth of a Salmonella fraB mutant in that same medium. For select organisms, the toxicity assay was cross-validated by direct mass spectrometry-aided measurement of F-Asn in the spent-culture media and through demonstration of FraB and FraD enzyme activity in cellular extracts. For prototrophs, F-Asn utilization was additionally confirmed by growth in a minimal medium containing F-Asn as the sole carbon source. Collectively, these studies established that Clostridiumbolteae, Clostridium acetobutylicum, and Clostridium clostridioforme can utilize F-Asn, but Clostridium difficile cannot; Klebsiella oxytoca and some Klebsiella pneumoniae subspecies can utilize F-Asn; and some Citrobacter rodentium and Citrobacter freundii strains can also utilize F-Asn. Within Salmonella enterica, the host-adapted serovars Typhi and Paratyphi A have lost the ability to utilize F-Asn.IMPORTANCE Fructose-asparagine (F-Asn) is a precursor to acrylamide that is found in human foods, and it is also a nutrient source for Salmonella enterica, a foodborne pathogen. Here, we determined that among the normal intestinal microbiota, there are species of Clostridium that encode the enzymes required for F-Asn utilization. Using complementary experimental approaches, we have confirmed that three members of Clostridium, two members of Klebsiella, and two members of Citrobacter can indeed utilize F-Asn. The Clostridium spp. likely compete with Salmonella for F-Asn in the gut and contribute to competitive exclusion. FraB, one of the enzymes in the F-Asn utilization pathway, is a potential drug target because inhibition of this enzyme leads to the accumulation of a toxic metabolite that inhibits the growth of Salmonella species. This study identifies the potential off-target organisms that need to be considered when developing therapeutics directed at FraB.

Dataset Information

Fructose-asparagine is a primary nutrient during growth of Salmonella in the inflamed intestine.

Publications

Fructose-asparagine is a primary nutrient during growth of Salmonella in the inflamed intestine.

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