Potential use of inhibitors of bacteria spore germination in the prophylactic treatment of anthrax and<i>Clostridium difficile</i>-associated disease

Alvarez, Zadkiel; Abel-Santos, Ernesto

doi:10.1586/14787210.5.5.783

Cited by 23 publications

(18 citation statements)

References 88 publications

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“…Spore germination is the first necessary step in the establishment of B. anthracis infection (15). Hence, inhibition of B. anthracis spore germination could serve as a prophylactic approach to prevent anthrax in exposed personnel (5). Antigermination therapy will delay infection onset and hence allow antibiotic and/or vaccine treatments to be more effective.…”

Section: Resultsmentioning

confidence: 99%

Testing Nucleoside Analogues as Inhibitors of Bacillus anthracis Spore Germination In Vitro and in Macrophage Cell Culture

Alvarez

Lee

Abel-Santos

2010

Antimicrob Agents Chemother

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Bacillus anthracis, the etiological agent of anthrax, has a dormant stage in its life cycle known as the endospore. When conditions become favorable, spores germinate and transform into vegetative bacteria. In inhalational anthrax, the most fatal manifestation of the disease, spores enter the organism through the respiratory tract and germinate in phagosomes of alveolar macrophages. Germinated cells can then produce toxins and establish infection. Thus, germination is a crucial step for the initiation of pathogenesis. B. anthracis spore germination is activated by a wide variety of amino acids and purine nucleosides. Inosine and L-alanine are the two most potent nutrient germinants in vitro. Recent studies have shown that germination can be hindered by isomers or structural analogues of germinants. 6-Thioguanosine (6-TG), a guanosine analogue, is able to inhibit germination and prevent B. anthracis toxin-mediated necrosis in murine macrophages. In this study, we screened 46 different nucleoside analogues as activators or inhibitors of B. anthracis spore germination in vitro. These compounds were also tested for their ability to protect the macrophage cell line J774a.1 from B. anthracis cytotoxicity. Structure-activity relationship analysis of activators and inhibitors clarified the binding mechanisms of nucleosides to B. anthracis spores. In contrast, no structure-activity relationships were apparent for compounds that protected macrophages from B. anthracis-mediated killing. However, multiple inhibitors additively protected macrophages from B. anthracis.

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Section: Resultsmentioning

confidence: 99%

Testing Nucleoside Analogues as Inhibitors of Bacillus anthracis Spore Germination In Vitro and in Macrophage Cell Culture

Alvarez

Lee

Abel-Santos

2010

Antimicrob Agents Chemother

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“…type B is closely related to surgeonfish intestinal symbionts that form multiple endospores to reproduce [12], it appears that type B cells may no longer have the genetic capacity to form a dormant and fully resistant endospore. Many intestinal anaerobes, from harmful pathogens to benign commensals, use endospores for effective dispersal between vertebrate hosts [8,10,92]. The ability of an intestinal bacterium to produce an endospore should be valuable to survival.…”

Section: Discussionmentioning

confidence: 99%

The genomic basis for the evolution of a novel form of cellular reproduction in the bacterium Epulopiscium

et al. 2012

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BackgroundEpulopiscium sp. type B, a large intestinal bacterial symbiont of the surgeonfish Naso tonganus, does not reproduce by binary fission. Instead, it forms multiple intracellular offspring using a process with morphological features similar to the survival strategy of endospore formation in other Firmicutes. We hypothesize that intracellular offspring formation in Epulopiscium evolved from endospore formation and these two developmental programs share molecular mechanisms that are responsible for the observed morphological similarities.ResultsTo test this, we sequenced the genome of Epulopiscium sp. type B to draft quality. Comparative analysis with the complete genome of its close, endospore-forming relative, Cellulosilyticum lentocellum, identified homologs of well-known sporulation genes characterized in Bacillus subtilis. Of the 147 highly conserved B. subtilis sporulation genes used in this analysis, we found 57 homologs in the Epulopiscium genome and 87 homologs in the C. lentocellum genome.ConclusionsGenes coding for components of the central regulatory network which govern the expression of forespore and mother-cell-specific sporulation genes and the machinery used for engulfment appear best conserved. Low conservation of genes expressed late in endospore formation, particularly those that confer resistance properties and encode germinant receptors, suggest that Epulopiscium has lost the ability to form a mature spore. Our findings provide a framework for understanding the evolution of a novel form of cellular reproduction.

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“…2–5 CDI typically occurs after the disruption of gut microbiota following a course of antibiotics and subsequent ingestion of C. difficile spores from the surrounding environment. 6 The current standard of care also relies on antibiotics. However, this strategy can perpetuate recurrence of CDI because it fails to eliminate C. difficile spores and results in further suppression of indigenous microbiota.…”

Section: Introductionmentioning

confidence: 99%

“…This approach builds on the natural mechanisms that control the lifecycle of C. difficile and has the advantage of not placing selective pressure on dividing cells, which may limit the potential of developing resistance. 6 Herein, we report the synthesis of modified bile acid derivatives of CDCA and UDCA. These compounds have been evaluated in optical density and microscope-based spore germination assays, and we have identified several analogues that are highly potent inhibitors of C. difficile spore germination.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination

et al. 2017

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Standard antibiotic-based strategies for the treatment of Clostridium difficile infections disrupt indigenous microbiota and commonly fail to eradicate bacterial spores, two key factors that allow recurrence of infection. As an alternative approach to controlling C. difficile infection, a series of bile acid derivatives have been prepared that inhibit taurocholate-induced spore germination. These analogues have been evaluated in a highly virulent NAP1 strain using optical density and phase-contrast microscopy assays. Heterocycle substitutions at C24 were well-tolerated and several tetrazole-containing derivatives were highly potent inhibitors in both assays, with complete inhibition of spore germination observed at 10–25 μM. To limit intestinal absorption, C7-sulfated analogues designed to avoid active and passive transport pathways were prepared. One of these derivatives, compound 21b, was found to be a potent inhibitor of C. difficile spore germination and poorly permeable in a Caco-2 model of intestinal epithelial absorption, suggesting that it is likely to be gut-restricted.

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Potential use of inhibitors of bacteria spore germination in the prophylactic treatment of anthrax andClostridium difficile-associated disease

Cited by 23 publications

References 88 publications

Testing Nucleoside Analogues as Inhibitors of Bacillus anthracis Spore Germination In Vitro and in Macrophage Cell Culture

Testing Nucleoside Analogues as Inhibitors of Bacillus anthracis Spore Germination In Vitro and in Macrophage Cell Culture

The genomic basis for the evolution of a novel form of cellular reproduction in the bacterium Epulopiscium

Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination

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