Inhibition of Sortase, a Bacterial Surface Protein Anchoring Transpeptidase, by β-Sitosterol-3-<i>O</i>-glucopyranoside from<i>Fritillaria verticillata</i>

Kim, Soo-Hwan; Shin, Dong Chun; Oh, Min-A; Chung, Soon‐Chun; Lee, Jang-Suk; Chang, Ikwhang; Oh, Ki‐Bong

doi:10.1271/bbb.67.2477

Cited by 63 publications

(40 citation statements)

References 16 publications

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“…inoculation of the pathogen (12,13). Earlier work used in vitro (inhibition of fluorogenic substrate cleavage) and virtual screening of compound libraries to identify sortase inhibitors (15,(52)(53)(54)(55)(56). Although these studies identified both competitive and noncompetitive inhibitors (57,58), isolated compounds have not yet been shown to inhibit in vivo sortase activity in staphylococci, i.e., the cleavage of sorting signals or the assembly of surface proteins into the bacterial cell wall (54,(59)(60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Zhang

Liu

Zhu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

139

145

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Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl) [1,2,4]

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Section: Discussionmentioning

confidence: 99%

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Zhang

Liu

Zhu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

139

145

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“…The extract from Fritillaria verticillata bulbs was subjected to silica gel chromatography, and a fraction with potent inhibitory effects on sortase was isolated. The constituent of this fraction was identified by NMR as glucosylsterol ␤-sitosterol-3-O-glucopyranol (93). As sitosterol alone does not inhibit sortase, it was concluded that the inhibitory effect must reside within the glucopyranoside moiety of the molecule.…”

Section: Sortase a Inhibitorsmentioning

confidence: 99%

Sortases and the Art of Anchoring Proteins to the Envelopes of Gram-Positive Bacteria

Marraffini

DeDent²,

Schneewind³

2006

Microbiol Mol Biol Rev

608

600

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SUMMARY The cell wall envelopes of gram-positive bacteria represent a surface organelle that not only functions as a cytoskeletal element but also promotes interactions between bacteria and their environment. Cell wall peptidoglycan is covalently and noncovalently decorated with teichoic acids, polysaccharides, and proteins. The sum of these molecular decorations provides bacterial envelopes with species- and strain-specific properties that are ultimately responsible for bacterial virulence, interactions with host immune systems, and the development of disease symptoms or successful outcomes of infections. Surface proteins typically carry two topogenic sequences, i.e., N-terminal signal peptides and C-terminal sorting signals. Sortases catalyze a transpeptidation reaction by first cleaving a surface protein substrate at the cell wall sorting signal. The resulting acyl enzyme intermediates between sortases and their substrates are then resolved by the nucleophilic attack of amino groups, typically provided by the cell wall cross bridges of peptidoglycan precursors. The surface protein linked to peptidoglycan is then incorporated into the envelope and displayed on the microbial surface. This review focuses on the mechanisms of surface protein anchoring to the cell wall envelope by sortases and the role that these enzymes play in bacterial physiology and pathogenesis.

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“…This work led to the identification of several compounds (summarized in Table 2) that demonstrate varying degrees of inhibition in vitro and in vivo. Most notable were the isoquinoline alkaloids from the rhizomes of Coptis chinensis (167) and β-sitosterol-3-Oglucopyranoside from Fritillaria verticillata, which were determined to have an IC 50 of 18.3 μg/mL and 15 μg/ml, respectively (168). These compounds demonstrated inhibition of sortase enzymatic activity in vitro, but their utilization in bacterial culture resulted in a growth defect (167,168).…”

Section: Small-molecule Inhibitors Of Sortasementioning

confidence: 99%

“…Most notable were the isoquinoline alkaloids from the rhizomes of Coptis chinensis (167) and β-sitosterol-3-Oglucopyranoside from Fritillaria verticillata, which were determined to have an IC 50 of 18.3 μg/mL and 15 μg/ml, respectively (168). These compounds demonstrated inhibition of sortase enzymatic activity in vitro, but their utilization in bacterial culture resulted in a growth defect (167,168). Given that a sortase A mutant behaves similarly to wild type when grown in culture, these findings suggest that some compounds may target more than one cellular process, resulting in the measured pleiotropic effects.…”

Section: Small-molecule Inhibitors Of Sortasementioning

confidence: 99%

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

2016

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Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

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Inhibition of Sortase, a Bacterial Surface Protein Anchoring Transpeptidase, by β-Sitosterol-3-O-glucopyranoside fromFritillaria verticillata

Cited by 63 publications

References 16 publications

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Sortases and the Art of Anchoring Proteins to the Envelopes of Gram-Positive Bacteria

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

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