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A metabolic intermediate of the fructose-asparagine utilization pathway inhibits growth of a Salmonella fraB mutant.


ABSTRACT: Insertions in the Salmonella enterica fra locus, which encodes the fructose-asparagine (F-Asn) utilization pathway, are highly attenuated in mouse models of inflammation (>1000-fold competitive index). Here, we report that F-Asn is bacteriostatic to a fraB mutant (IC50 19??M), but not to the wild-type or a fra island deletion mutant. We hypothesized that the presence of FraD kinase and absence of FraB deglycase causes build-up of a toxic metabolite: 6-phosphofructose-aspartate (6-P-F-Asp). We used biochemical assays to assess FraB and FraD activities, and mass spectrometry to confirm that the fraB mutant accumulates 6-P-F-Asp. These results, together with our finding that mutants lacking fraD or the fra island are not attenuated in mice, suggest that the extreme attenuation of a fraB mutant stems from 6-P-F-Asp toxicity. Salmonella FraB is therefore an excellent drug target, a prospect strengthened by the absence of the fra locus in most of the gut microbiota.

SUBMITTER: Sabag-Daigle A 

PROVIDER: S-EPMC4941530 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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A metabolic intermediate of the fructose-asparagine utilization pathway inhibits growth of a Salmonella fraB mutant.

Sabag-Daigle Anice A   Blunk Henry M HM   Sengupta Anindita A   Wu Jikang J   Bogard Alexander J AJ   Ali Mohamed M MM   Stahl Christopher C   Wysocki Vicki H VH   Gopalan Venkat V   Behrman Edward J EJ   Ahmer Brian M M BM  

Scientific reports 20160712


Insertions in the Salmonella enterica fra locus, which encodes the fructose-asparagine (F-Asn) utilization pathway, are highly attenuated in mouse models of inflammation (>1000-fold competitive index). Here, we report that F-Asn is bacteriostatic to a fraB mutant (IC50 19 μM), but not to the wild-type or a fra island deletion mutant. We hypothesized that the presence of FraD kinase and absence of FraB deglycase causes build-up of a toxic metabolite: 6-phosphofructose-aspartate (6-P-F-Asp). We us  ...[more]

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