Vinyl Sulfones:  Inhibitors of SrtA, a Transpeptidase Required for Cell Wall Protein Anchoring and Virulence in <i>Staphylococcus aureus</i>

Frankel, Brenda A.; Bentley, Matthew L.; Kruger, Ryan G.; McCafferty, Dewey G.

doi:10.1021/ja0390294

Cited by 191 publications

(105 citation statements)

References 27 publications

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“…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). Many of the isolated compounds diminish or block staphylococcal growth, indicating that they cannot function as selective inhibitors of S. aureus sortase (53,61,63,64).…”

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.

134

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.

134

145

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“…These peptide-derived inhibitors display favorable K i values, however their rates of inactivation are slow. Vinyl sulfones also react with thiols, but the corresponding peptide vinyl sulfones present even slower rates of sortase inactivation than diazoketone or chloromethylketone derivatives (17). Finally, phosphorous isosteres of peptides are effective transition state analogs and inhibitors of zinc proteases.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of sortases by small molecules may therefore function as a therapeutic strategy for bacterial infections. Previous work described several sortase inhibitors, including methane-thiosulfonates (12), peptide substrate-derived affinity labels (13), natural compounds (14 -16), vinyl sulfones (17), diarylacrylonitriles (18), bis(indole) alkaloids (19), peptidomimetics (20), isoquinoline alkaloids (16), and threonine analogues (21). However, most of these compounds are either of low activity, lack specificity, or display undesirable structural features that confound therapeutic use.…”

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confidence: 99%

Activation of Inhibitors by Sortase Triggers Irreversible Modification of the Active Site

Maresso

Kern

et al. 2007

Journal of Biological Chemistry

101

106

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Sortases anchor surface proteins to the cell wall of Gram-positive pathogens through recognition of specific motif sequences. Loss of sortase leads to large reductions in virulence, which identifies sortase as a target for the development of antibacterials. By screening 135,625 small molecules for inhibition, we report here that aryl (␤-amino)ethyl ketones inhibit sortase enzymes from staphylococci and bacilli. Inhibition of sortases occurs through an irreversible, covalent modification of their active site cysteine. Sortases specifically activate this class of molecules via ␤-elimination, generating a reactive olefin intermediate that covalently modifies the cysteine thiol. Analysis of the three-dimensional structure of Bacillus anthracis sortase B with and without inhibitor provides insights into the mechanism of inhibition and reveals binding pockets that can be exploited for drug discovery.The emergence of bacterial strains resistant to antibiotic therapy is a major public health threat (1). Of particular concern is Staphylococcus aureus, because this Gram-positive pathogen is the leading cause of infections in the bloodstream, lower respiratory tract, skin, and soft tissue in the United States (2). S. aureus strains exhibiting resistance against multiple antibiotics, such as methicillin-resistant S. aureus, are isolated in 30 -60% of community and Ͼ80% of hospital infections with this pathogen (3). Vancomycin or other glycopeptides are considered last-resort therapies for methicillin-resistant S. aureus; however, S. aureus strains with intermediate or full resistance to vancomycin can cause infections for which antimicrobial treatment may no longer be effective (4).Surface proteins of Gram-positive bacteria play important roles during pathogenesis (5). Sortases anchor these polypeptides to the bacterial cell wall envelope (6). For example, S. aureus sortase A recognizes proteins destined for the cell surface via an LPXTG motif in their C-terminal sorting signal (7). Following cleavage between the threonine and the glycine residues, an acyl-enzyme intermediate captures cleaved substrate at the active site thiol of sortase (8). Nucleophilic attack of the amino group of the peptidoglycan precursor lipid II (at the thioester intermediate resolves the acyl enzyme and forms an amide bond between the C-terminal threonine of surface protein and pentaglycine crossbridges (9). Lipid II-linked polypeptide is subsequently incorporated into the cell wall envelope of staphylococci (10). The final product of this pathway, protein linked to cell wall pentaglycine cross-bridges, is displayed on the bacterial surface and enables interactions between the pathogen and tissues of its host.Surface protein anchoring to the cell wall envelope is thought to be an essential strategy for bacterial survival during infection, because mutants lacking genes for one or more sortase enzymes are attenuated in virulence (11). Inhibition of sortases by small molecules may therefore function as a therapeutic strategy for bacterial infections. ...

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“…Sortase is also involved in the assembly of cell surface pili on Gram-positive bacteria, which often aid attachment to host cells (Ton-That & Schneewind 2003). Collectively, these and other findings suggest that sortases are promising targets for new antibacterial drugs (Schneewind et al 1993, Frankel et al 2004, Ton-That et al 2004, Weiss et al 2004, Zink & Burns 2005. However, there have been few studies focused on the development of specific inhibitors of sortases for the treatment of Gram-positive bacterial infections.…”

Section: Resale or Republication Not Permitted Without Written Consenmentioning

confidence: 99%

Sortase inhibitor phenyl vinyl sulfone inhibits Renibacterium salmoninarum adherence and invasion of host cells

Sudheesh¹,

Crane²,

Cain³

et al. 2007

Dis. Aquat. Org.

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Renibacterium salmoninarum, the causative agent of bacterial kidney disease in salmonid fishes, is a Gram-positive diplococcobacillus belonging to the family Micrococcaceae. Analysis of the genome sequence of the bacterium demonstrated the presence of a sortase homolog (srtD), a gene specifying an enzyme found in Gram-positive bacteria and required for covalent anchoring of cell surface proteins. Interference of sortase activity is being examined as a target for therapeutic prevention of infection by several pathogenic Gram-positive bacterial species. In silico analysis identified 8 open reading frames containing sortase recognition motifs, suggesting these proteins are translocated to the bacterial cell wall. The sortase and potential sortase substrate genes are transcribed in R. salmoninarum, suggesting they encode functional proteins. Treatment of R. salmoninarum with phenyl vinyl sulfone (PVS) significantly reduced bacterial adherence to Chinook salmon fibronectin. In addition, the ability of the PVS-treated bacteria to adhere to Chinook salmon embryo cells in vitro was dramatically reduced compared to that of untreated bacteria. More importantly, PVS-treated bacteria were unable to invade and replicate within CHSE-214 cells (demonstrated by an intracellular growth assay and by light microscopy). When treated with PVS, R. salmoninarum was not cytopathic to CHSE-214 cells, whereas untreated bacteria produced cytopathology within a few days. These findings clearly show that PVS, a small molecule drug and a known sortase inhibitor, can interfere with the ability of R. salmoninarum to adhere and colonize fish cells, with a corresponding decrease in virulence.KEY WORDS: Renibacterium salmoninarum · Bacterial kidney disease · Anti-virulence chemotherapy · Adherence · Invasion · Host cell sortase inhibitor · Phenyl vinyl sulfone Resale or republication not permitted without written consent of the publisherDis Aquat Org 78: [115][116][117][118][119][120][121][122][123][124][125][126][127] 2007 1994, Kehoe 1994). MSCRAMs have specific C-terminal anchoring signals or cell wall sorting (CWS)-motifs that are recognized by a membrane transpeptidase called sortase. Sortase catalyzes covalent anchoring of these proteins to the peptidoglycan surface during cell wall synthesis (reviewed in Navarre & Schneewind 1999, Ton-That et al. 2004, Marraffini et al. 2006). Elimination of sortase activity and the consequent disruption of surface protein anchoring correlates with a dramatic decrease in pathogenicity of Gram-positive bacteria in animal infections (Mazmanian et al. 2000, Bolken et al. 2001, Bierne et al. 2002, Garandeau et al. 2002, Jonsson et al. 2002, Weiss et al. 2004. Sortase is also involved in the assembly of cell surface pili on Gram-positive bacteria, which often aid attachment to host cells (Ton-That & Schneewind 2003). Collectively, these and other findings suggest that sortases are promising targets for new antibacterial drugs (Schneewind et al. 1993, Frankel et al. 2004, Ton-That et al. 2004, Weis...

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Vinyl Sulfones: Inhibitors of SrtA, a Transpeptidase Required for Cell Wall Protein Anchoring and Virulence in Staphylococcus aureus

Cited by 191 publications

References 27 publications

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Activation of Inhibitors by Sortase Triggers Irreversible Modification of the Active Site

Sortase inhibitor phenyl vinyl sulfone inhibits Renibacterium salmoninarum adherence and invasion of host cells

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