Abstract
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 (beta-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 beta-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.
Highlights
Surface proteins of Gram-positive bacteria play important roles during pathogenesis [5]
Screening for Sortase Inhibitors—A biochemical assay that monitors S. aureus sortase A cleavage of the fluorescence resonance energy transfer substrate (a-LPETG-d) between the threonine and glycine residues was optimized for HTS [8]
Antibiotic resistance has been observed in other Gram-positive bacteria, including an agent of bioterrorism, B. anthracis [44]
Summary
Surface proteins of Gram-positive bacteria play important roles during pathogenesis [5]. Inhibition by AAEKs Occurs at the Active Site Thiol of Sortase— S. aureus sortase A was incubated with or without AAEK1. The structures of ten representatives from the AAEK chemotype class The mean percent inhibitions of sortase A (S. aureus and B. anthracis) and papain (C. papaya) are presented.
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