Structure-Based Design of Sortase Inhibitors for Anti-Infective Therapy

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DESCRIPTION (provided by applicant): The emergence of drug-resistant bacteria is an increasing health problem. Because of the resistance challenge, novel approaches which will not be subject to existing resistance mechanisms, are required for antimicrobial drug discovery. Targeting bacterial virulence for antimicrobial chemotherapy is an effective approach for bacterial infection. Sortase A is an attractive and validated antivirulent target, which catalyzes anchoring surface proteins on the bacterial cell membrane. Surface proteins contribute to bacterial adhesion, evasion of host immune response, nutrient acquisition and host cell invasion. Interference with the display of surface proteins on the bacterial cell membrane by inhibition of sortase A is an effective mechanistic approach to antibacterial therapy. Currently, no sortase inhibitors have been approved for treatment of bacterial infection. The overall goal of this project is to discover and develop small molecule inhibitors of sortase for anti-infective therapy. Our strategy is to use structure-based drug design (SBDD) to identify potent drug-like small molecules in a recombinant SrtA assay and a fibronectin-binding assay and position them for development into drugs for the treatment of Gram-positive bacterial infections. This strategy represents an innovative approach to the treatment of Gram-positive bacterial infections that will increase the efficacy of existing antibiotics at low doses, and decrease the development of antibiotic resistance. In preliminary studies, we have used the co-crystal structural information generated for Staphylococcus aureus SrtA and designed two classes of sortase A inhibitors based on a vinyl sulfone warhead template. Molecular modeling studies suggest that these two classes of vinyl sulfones will inactivate sortase by forming a reversible, covalent bond with the active site cysteine thiol functionality. The major milestone of this proposal will be the identification of selective lead compounds with potent sortase A inhibition (IC50 < 1 ?M) and low cytotoxicity (CC50 > 100 1 ?M). Lead compounds will display selectivity against a battery of profiling enzymes and will be pharmacokinetically acceptable in in vitro studies. Phase II will continue the development of these lead compounds and lead to the identification of a Clinical Development Candidate (CDC). PUBLIC HEALTH RELEVANCE: The overall goal of this project is to identify potent drug-like small molecules in a recombinant sortase A assay and a fibronectin-binding assay and position them for development them into drugs for the treatment of Gram-positive bacterial infections. Our strategy is to use structure- based drug design (SBDD) to define these inhibitors of sortase A. We will define sortase A inhibitors that are potent, selective in a battery of profiling enzymes, non-cytotoxic and exhibit favorable in vitro pharmacokinetic properties.