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

Article scientifique 2016 Anglais

Résumé

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 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.

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Sabag-Daigle, A., Blunk, H., Sengupta, A., Wu, J., Bogard, A., Ali, M., Stahl, C., Wysocki, V., Gopalan, V., Behrman, E., Ahmer, B. (2016). A metabolic intermediate of the fructose-asparagine utilization pathway inhibits growth of a Salmonella fraB mutant. https://doi.org/10.1038/srep28117

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Auteur(s)

Anice Sabag-Daigle Henry M. Blunk Anindita Sengupta Jikang Wu Alexander J. Bogard Mohamed Medhat Ali Christopher C. Stahl Vicki H. Wysocki Venkat Gopalan Edward J. Behrman Brian M. M. Ahmer

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