The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens

Kalera, Karishma; Stothard, Alicyn I; Woodruff, Peter J.; Swarts, Benjamin M.

doi:10.1039/d0cc04955g

Cited by 16 publications

(21 citation statements)

References 140 publications

(286 reference statements)

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“…These CRs can form active sites that usually have loops. CDs of GH enzymes contain well-known trehalase signature motifs, motif 1 (PGGRFXEXY[G/Y] D[S/T] Y] and motif 2 (QWD[Y/F]PN/Y) [G/A] W[P/A] P), whereas GH65 and GH15 trehalases do not [ 48 , 49 ]. Our Antarctica isolate S .…”

Section: Resultsmentioning

confidence: 99%

“…Due to the acquisition of an additional cluster of trehalose metabolism genes, namely a second PTS that mediates high-efficiency trehalose uptake from the environment, epidemic C. difficile strains can also grow on low trehalose. By increasing toxin levels, both modified trehalose utilization systems contributed to the growth and toxicity of these epidemic C. difficile strains [ 49 ]. There have been no previous papers on the function of the trehalose degradation pathway in virulence in Antarctic isolates till date.…”

Section: Resultsmentioning

confidence: 99%

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In silico analysis and a comparative genomics approach to predict pathogenic trehalase genes in the complete genome of Antarctica Shigella sp. PAMC28760

et al. 2022

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Although four Shigella species ( S. flexneri, S . sonnei , S. dysenteriae , and S. boydii ) have been reported, S . sp. PAMC 28760, an Antarctica isolate, is the only one with a complete genome deposited in NCBI database as an uncharacterized isolate. Because it is the world’s driest, windiest, and coldest continent, Antarctica provides an unfavourable environment for microorganisms. Computational analysis of genomic sequences of four Shigella species and our uncategorized Antarctica isolates Shigella sp. PAMC28760 was performed using MP3 (offline version) program to predict trehalase encoding genes as a pathogenic or non-pathogenic form. Additionally, we employed RAST and Prokka (offline version) annotation programs to determine locations of periplasmic ( treA ) and cytoplasmic ( treF ) trehalase genes in studied genomes. Our results showed that only 56 out of 134 Shigella strains had two different trehalase genes ( treF and treA ). It was revealed that the treF gene tends to be prevalent in Shigella species. In addition, both treA and treF genes were present in our strain S . sp. PAMC28760. The main objective of this study was to predict the prevalence of two different trehalase genes ( treF and treA ) in the complete genome of Shigella sp. PAMC28760 and other complete genomes of Shigella species. Till date, it is the first study to show that two types of trehalase genes are involved in Shigella species, which could offer insight on how the bacteria use accessible carbohydrate like glucose produced from the trehalose degradation pathway, and importance of periplasmic trehalase involvement in bacterial virulence.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In silico analysis and a comparative genomics approach to predict pathogenic trehalase genes in the complete genome of Antarctica Shigella sp. PAMC28760

et al. 2022

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“…The recombinant transketolase from S. elongatus was used as robust catalyst, and especially stereoselective sugar synthesis benefits from chemoenzymatic strategies. [42] Thus, five new 7dSh analogues (2-6) originated from this approach, whereby four turned out to be in vitro inhibitors of the A. thaliana DHQS in a micromolar range. Modification of the C-5 residue confirmed that the amount of pyranosyl form of the inhibitor and the presence of the hydroxyl group at C-5 with the correct stereo configuration are equal antagonists in this SAR study.…”

Section: Discussionmentioning

confidence: 99%

“…This straightforward approach enabled us to expand the novel compound family of 7dSh analogues, a potential herbicide class which demands a chemical structure‐activity relationship study with careful transport and plant assays. The recombinant transketolase from S. elongatus was used as robust catalyst, and especially stereoselective sugar synthesis benefits from chemoenzymatic strategies [42] . Thus, five new 7dSh analogues ( 2 – 6 ) originated from this approach, whereby four turned out to be in vitro inhibitors of the A. thaliana DHQS in a micromolar range.…”

Section: Discussionmentioning

confidence: 99%

Hybrid Chemoenzymatic Synthesis of C₇‐Sugars for Molecular Evidence of in vivo Shikimate Pathway Inhibition

et al. 2022

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The design of distinctive chemical synthesis strategies aims for the most efficient routes towards versatile compounds in drug target studies. Here, we establish a powerful hybrid synthetic approach of total chemical and chemoenzymatic synthesis to efficiently obtain various 7-deoxy-sedoheptulose (7dSh, 1) analogues, unique C 7 sugars, for structure-activity relationship studies. 7dSh (1) is a rare microbial sugar with in planta herbicidal activity. As natural antimetabolite of 3-dehydroquinate synthase (DHQS), 7dSh (1) inhibits the shikimate pathway, which is essential for the synthesis of aromatic amino acids in bacteria, fungi, and plants, but absent in mammals. As glyphosate, the most used chemical herbicide faces restrictions worldwide, DHQS has gained more attention as valid target of herbicides and antimicrobial agents. In vitro and in vivo analyses of the C 7 -deoxysugars confirm DHQS as enzymatic target, highlight the crucial role of uptake for inhibition and add molecular aspects to target mechanism studies of C 7 -sugars as our contribution to global efforts for alternative weed-control strategies.

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“…The chemoenzymatic synthesis of other trehalose analogs has been reported previously. [73,74] We are now analyzing the genomic DNA sequence of the producing strain and trying to find the enzymes to biosynthesize 4-trehalosamine. If the producing enzymes become applicable, significant amounts of 4-trehalosamine could be produced from starch and some nitrogen sources at a low cost, similar to the current mass production of trehalose.…”

Section: Mass Producibility Of 4-trehalosaminementioning

confidence: 99%

Rediscovery of 4‐Trehalosamine as a Biologically Stable, Mass‐Producible, and Chemically Modifiable Trehalose Analog

et al. 2022

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Nonreducing disaccharide trehalose is used as a stabilizer and humectant in various products and is a potential medicinal drug, showing curative effects on the animal models of various diseases. However, its use is limited as it is hydrolyzed by trehalase, a widely expressed enzyme in multiple organisms. Several trehalose analogs are prepared, including a microbial metabolite 4‐trehalosamine, and their high biological stability is confirmed. For further analysis, 4‐trehalosamine is selected as it shows high producibility. Compared with trehalose, 4‐trehalosamine exhibits better or comparable protective activities and a high buffer capacity around the neutral pH. Another advantage of 4‐trehalosamine is its chemical modifiability: simple reactions produce its various derivatives. Labeled probes and detergents are synthesized in one‐pot reactions to exemplify the feasibility of their production, and their utility is confirmed for their respective applications. The labeled probes are used for mycobacterial staining. Although the derivative detergents can be effectively used in membrane protein research, long‐chain detergents show 1000–3000‐fold stronger autophagy‐inducing activity in cultured cells than trehalose and are expected to become a drug lead and research reagent. These results indicate that 4‐trehalosamine is a useful trehalose substitute for various purposes and a material to produce new useful derivative substances.

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The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens

Abstract: Trehalose, a disaccharide of glucose, is increasingly recognized as an important contributor to virulence in major bacterial pathogens, such as Mycobacterium tuberculosis, Clostridioides difficile, and Burkholderia pseudomallei. Accordingly, bacterial trehalose...

Cited by 16 publications

References 140 publications

In silico analysis and a comparative genomics approach to predict pathogenic trehalase genes in the complete genome of Antarctica Shigella sp. PAMC28760

In silico analysis and a comparative genomics approach to predict pathogenic trehalase genes in the complete genome of Antarctica Shigella sp. PAMC28760

Hybrid Chemoenzymatic Synthesis of C₇‐Sugars for Molecular Evidence of in vivo Shikimate Pathway Inhibition

Rediscovery of 4‐Trehalosamine as a Biologically Stable, Mass‐Producible, and Chemically Modifiable Trehalose Analog

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The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens

Abstract: Trehalose, a disaccharide of glucose, is increasingly recognized as an important contributor to virulence in major bacterial pathogens, such as Mycobacterium tuberculosis, Clostridioides difficile, and Burkholderia pseudomallei. Accordingly, bacterial trehalose...

Cited by 16 publications

References 140 publications

In silico analysis and a comparative genomics approach to predict pathogenic trehalase genes in the complete genome of Antarctica Shigella sp. PAMC28760

In silico analysis and a comparative genomics approach to predict pathogenic trehalase genes in the complete genome of Antarctica Shigella sp. PAMC28760

Hybrid Chemoenzymatic Synthesis of C7‐Sugars for Molecular Evidence of in vivo Shikimate Pathway Inhibition

Rediscovery of 4‐Trehalosamine as a Biologically Stable, Mass‐Producible, and Chemically Modifiable Trehalose Analog

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Product

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Hybrid Chemoenzymatic Synthesis of C₇‐Sugars for Molecular Evidence of in vivo Shikimate Pathway Inhibition