Dataset Information

Degradation-resistant trehalose analogues block utilization of trehalose by hypervirulent Clostridioides difficile.

ABSTRACT: Trehalose is used as an additive in thousands of foods, cosmetics, and pharmaceutical products, and it is being investigated as a therapeutic for multiple human diseases. However, its ability to be used as a carbon source by microbes is a concern, as highlighted by the recent finding that trehalose can be metabolized by and potentially enhance the virulence of epidemic Clostridioides difficile. Here, we show that trehalose analogues designed to resist enzymatic degradation are incapable of being used as carbon sources by C. difficile. Furthermore, we demonstrate that trehalose analogues, but not the known trehalase inhibitor validamycin A, inhibit native trehalose utilization by hypervirulent C. difficile. Thus, degradation-resistant trehalose analogues are valuable as trehalase inhibitors and as surrogates for or co-additives with trehalose in applications where enzymatic breakdown is a concern.

SUBMITTER: Danielson ND

PROVIDER: S-EPMC6499371 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Degradation-resistant trehalose analogues block utilization of trehalose by hypervirulent Clostridioides difficile.

Danielson Noah D ND Collins James J Stothard Alicyn I AI Dong Qing Qing QQ Kalera Karishma K Woodruff Peter J PJ DeBosch Brian J BJ Britton Robert A RA Swarts Benjamin M BM

Chemical communications (Cambridge, England) 20190401 34

Trehalose is used as an additive in thousands of foods, cosmetics, and pharmaceutical products, and it is being investigated as a therapeutic for multiple human diseases. However, its ability to be used as a carbon source by microbes is a concern, as highlighted by the recent finding that trehalose can be metabolized by and potentially enhance the virulence of epidemic Clostridioides difficile. Here, we show that trehalose analogues designed to resist enzymatic degradation are incapable of being ...[more]

PMID: 30968891

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Project description:The response to iron limitation of several bacteria is regulated by the ferric uptake regulator (Fur). The Fur-regulated transcriptional, translational and metabolic networks of the Gram-positive, pathogen Clostridioides difficile were investigated by a combined RNA sequencing, proteomic, metabolomic and electron microscopy approach. At high iron conditions (760 g/l) the C. difficile fur mutant displayed a growth deficiency compared to wild type C. difficile cells. Several iron transporters were found induced by Fur regulation during low iron (11 g/l) conditions. The major adaptation to low iron conditions was observed for the central energy metabolism. Most ferredoxin-dependent amino acid fermentations were found significantly down regulated (had, etf, acd, grd, trx, bdc, hbd). The substrates of these pathways phenylalanine, leucine, glycine and some initial intermediates (phenylpyruvate, oxo-isocaproate, 3-hydroxy-butanoyl-CoA, crotonyl-CoA) were found accumulated, while some end product like isocaproate and butanoate were found reduced. Flavodoxin (fldX) formation and riboflavin biosynthesis (rib) were found enhanced, most likely to replace the missing ferredoxins. Proline reductase (prd), the corresponding ion pumping RNF complex (rnf) and the reaction product 5-aminovalerate were significantly enhanced. An ATP forming ATPase (atpCDGAHFEB,) of the F0F1-type was found induced while the formation of a V-type, mostly proton-pumping, ATP-consuming ATPase (atpDBAFCEKI, was decreased. The [Fe-S] enzyme-dependent pyruvate formate lyase (pfl), formate dehydrogenase (fdh) and hydrogenase (hyd) branch of glucose utilization and glycogen biosynthesis (glg) were significantly reduced, leading to an accumulation of glucose and pyruvate. The formation of [Fe-S] enzyme carbon monoxide dehydrogenase (coo) was inhibited. An intensive remodeling of the cell wall was observed most likely to increase antibiotic resistance. Polyamine biosynthesis (spe) was found induced leading to an accumulation of spermine, spermidine and putrescine. The fur mutant lost most of its flagella. Finally, the CRISPR/Cas and a prophage encoding operon were downregulated. Fur binding sites were found upstream of 20 of the regulated genes. Overall, adaptation to low iron conditions in C. difficile focused on an increase of iron import, significant decrease in metabolic iron utilization and protection during the complex transition.

Dataset Information

Degradation-resistant trehalose analogues block utilization of trehalose by hypervirulent Clostridioides difficile.

Publications

Degradation-resistant trehalose analogues block utilization of trehalose by hypervirulent Clostridioides difficile.

Similar Datasets

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