Method for identifying inhibitors of staphylococcus aureus

Abstract

Provided are methods for identifying and/or designing inhibitors of Staphylococcus aureus biological activity. Also provided is a computer readable medium encoded with instructions executable by a CPU for performing the functions of identifying or designing inhibitors of Staphylococcus aureus biological activity, and a system comprising the computer readable medium and a CPU. Also provided are compounds identified and/or designed by the methods, methods of treatment including the compounds, methods of inhibiting S. aureus using the compounds, medicaments including the compounds for use in the treatment of S. aureus infection, or conditions related to S. aureus infection, and pharmaceutical compositions including the compounds. Methods for identifying a bacterial cell that is resistant to methicillin are also provided.

1 . A method for identifying a candidate inhibitor that binds to a site of  Staphylococcus aureus  ( S. aureus ) dihydrodipicolinate synthase (DapA) or a homologue or active fragment thereof, comprising:
 obtaining the structure coordinates of amino acids of DapA or a homologue or active fragment thereof;   generating a three-dimensional model of DapA or a homologue or active fragment thereof using the structure coordinates of the amino acids of DapA, wherein the model comprises a root mean square deviation from backbone atoms of said amino acids of not more than ±1.0 A;   determining a binding site of DapA or a homologue or active fragment thereof from the three-dimensional model, and   performing a computer fitting analysis to identify the candidate inhibitor that interacts with the binding site.   
     
     
         2 . The method of  claim 1 , wherein the  S. aureus  DapA or active fragment thereof is from a methicillin resistant  S. aureus  (MRSA) strain. 
     
     
         3 . The method of  claim 1 , wherein the binding site of DapA or homologue or active fragment thereof comprises the L-Lysine binding pocket. 
     
     
         4 . The method of  claim 3 , wherein the L-Lysine binding pocket comprises amino acid residue Lysine-86 of SEQ ID NO: 1. 
     
     
         5 . The method of  claim 3 , wherein the L-Lysine binding pocket comprises amino acid residues Ser-50, Lys-56, Asn-82, Lys-86 and Tyr-108 of SEQ ID NO:1. 
     
     
         6 . The method of  claim 1 , further comprising contacting the identified candidate inhibitor with DapA or homologue or active fragment thereof under conditions that allow for determination the effect of the inhibitor on  S. aureus  biological activity. 
     
     
         7 . The method of  claim 1 , wherein the fitting analysis of the interaction between the candidate inhibitor and the binding site predicts that the inhibitor will bind to the L-Lysine binding pocket with a binding affinity greater than or equal to the binding affinity for L-Lysine. 
     
     
         8 - 20 . (canceled)