Discovery of Diarylacrylonitriles as a Novel Series of Small Molecule Sortase A Inhibitors

Oh, Ki Bong; Kim, Soo Hwan; Lee, Jae Kwang; Cho, Won Jea; Lee, Tae Ho; Kim, Sang Hee

doi:10.1021/jm0498708

Cited by 116 publications

(104 citation statements)

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“…Previous studies on small molecule inhibitors of sortases have been limited to the screening of 1000 compounds, which identified diarylacrylonitriles as potential inhibitors (18). In this study, compounds with IC 50 values between 10 and 1000 M were reported, and one compound functioned as competitive inhibitor with very favorable K i value (18).…”

Section: Discussionmentioning

confidence: 84%

“…In this study, compounds with IC 50 values between 10 and 1000 M were reported, and one compound functioned as competitive inhibitor with very favorable K i value (18). Diarylacrylonitriles have been proposed to bind to the active site of sortase, although this hypothesis has not yet been supported by experimental evidence (18).…”

Section: Discussionmentioning

confidence: 95%

“…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%

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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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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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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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“…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%

“…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). Thus, the efficacy of sortase inhibitors as antiinfective therapeutics was heretofore not demonstrated (62,65).…”

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.

132

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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Cobalt(III)‐Catalyzed Construction of Benzofurans, Benzofuranones and One‐Pot Orthogonal C−H Functionalizations to Access Polysubstituted Benzofurans

et al. 2018

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Benzofuran and benzofuranone derivatives have been synthesized through exclusive 5-exo-dig intramolecular hydroarylation using the amide-directed, cost-effective, high-valent Cp*Co III -catalytic system. Challenging one-pot, orthogonal CÀH functionalizations using two different electrophiles are also reported to afford polysubstituted benzofurans. Several valuable functional group interconversions along with removal of the amide directing group provide a route to access several diversely functionalized benzofurans. The mechanistic study suggests a reversible cobaltation step is operative here.

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Discovery of Diarylacrylonitriles as a Novel Series of Small Molecule Sortase A Inhibitors

Abstract: On the basis of a hit from random screening, a novel class of small-molecule sortase A inhibitors was generated. The primary structure-activity relationship and the minimal structural requirements for potency were established through structural modifications and molecular modeling studies.

Cited by 116 publications

References 23 publications

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

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

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Cobalt(III)‐Catalyzed Construction of Benzofurans, Benzofuranones and One‐Pot Orthogonal C−H Functionalizations to Access Polysubstituted Benzofurans

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