Bridge-helix cap: target and method for inhibition of bacterial rna polymerase

Abstract

It has been discovered that the Sal target represents a new and promising target for antibacterial drug discovery. The Sal target is distinct from the rifamycin target and from the CBR703 target. This indicates that antibacterial compounds that function through the Sal target should exhibit no, or minimal, cross-resistance with rifamycins and CBR703. This further implies that it should be possible to co-administer antibacterial compounds that function through the Sal target together with a rifamycin, together with CBR703, or together with both a rifamycin and CBR703, in order to achieve additive or synergistic antibacterial effects and in order to suppress or eliminate the emergence of resistance.

What is claimed is: 
     
         1 . A method to treat a bacterial infection in a subject in need thereof, comprising administering to the subject a first compound selected as being an inhibitor of growth of a bacterium by binding to the bridge-helix cap target of an RNA polymerase, and a second compound that inhibits growth of a bacterium by binding to a site other than the bridge-helix cap target of an RNA polymerase. 
     
     
         2 . The method of  claim 1 , wherein the first compound is salinamide A. 
     
     
         3 . The method of  claim 1 , wherein the second compound is a rifamycin or CBR703. 
     
     
         4 . The method of  claim 3 , wherein the second compound is rifampin or CBR703. 
     
     
         5 . The method of  claim 1 , further comprising administering a third compound that inhibits growth of a bacterium by binding to a site other than the bridge-helix cap target of an RNA polymerase. 
     
     
         6 . The method of  claim 1 , wherein the first and second compounds are administered concurrently. 
     
     
         7 . The method of  claim 1 , wherein the first and second compounds are administered sequentially. 
     
     
         8 . The method of  claim 5 , wherein the third compound is administered concurrently with the first or second compound, or concurrently with the first and second compound. 
     
     
         9 . The method of  claim 5 , wherein the third compound is administered sequentially. 
     
     
         10 . A composition that comprises salinamide A and a rifamycin and/or CBR703. 
     
     
         11 . The composition of  claim 10  that comprises salinamide A and rifampin and/or CBR703. 
     
     
         12 . The composition of  claim 10  that comprises salinamide A and a rifamycin. 
     
     
         13 . The composition of  claim 12  that comprises salinamide A and rifampin. 
     
     
         14 . The composition of  claim 10  that comprises salinamide A and CBR703. 
     
     
         15 . The composition of  claim 10  that comprises salinamide A, a rifamycin, and CBR703. 
     
     
         16 . The composition of  claim 15  that comprises salinamide A, rifampin, and CBR703.