Bipartite inhibitors of bacterial RNA polymerase
The invention provides bipartite inhibitors of bacterial RNA polymerase having the general structural formula (I): X-α-Y (I) wherein X is an moiety that binds to the rifamycin binding site of a bacterial RNA polymerase, Y is a moiety that binds to the GE23077 binding site of a bacterial RNA polymerase, and α is a linker. The invention also provides compositions comprising such compounds, methods of making such compounds, and methods of using said compounds. The invention has applications in control of bacterial gene expression, control of bacterial growth, antibacterial chemistry, and antibacterial therapy.
1. A method for treating a bacterial infection in a mammal caused by methicillin-susceptible Staphylococcus aureus , methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium , or Acinetobacter baumannii comprising administering to the mammal an effective amount of a compound of formula (I):
X-α-Y (I)
or a pharmaceutically acceptable salt thereof, wherein:
a) X is a rifamycin or a rifamycin derivative that binds to the Rif target of a bacterial RNA polymerase; Y is a moiety that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker, wherein X is bonded to α through C3 of the rifamycin fused ring system, a moiety pendant from C3 of the rifamycin fused ring system, C4 of the rifamycin fused ring system, a moiety pendant from C4 of the rifamycin fused ring system, C11 of the rifamycin fused ring system, or a moiety pendant from C11 of the rifamycin fused ring system; or
b) X is a sorangicin or a sorangicin derivative that binds to the Rif target of a bacterial RNA polymerase; Y is a moiety that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker; or
c) X is a moiety that binds to the Rif target of a bacterial RNA polymerase; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker; or
d) X is a moiety that binds to the Rif target of a bacterial RNA polymerase; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker, wherein Y is bonded to α through a residue corresponding in position to the acyl-Apa residue of GE23077 or the Ama residue of GE23077; or
e) X is a moiety that binds to the Rif target of a bacterial RNA polymerase; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker, wherein Y is bonded to α through a residue corresponding in position to the acyl-Apa residue of GE23077; or
f) X is a moiety that binds to the Rif target of a bacterial RNA polymerase and is selected from the group consisting of rifamycin S, rifamycin SV, and sorangicin A; Y is GE23077; and α is a linker; or
g) X is a moiety that binds to the Rif target of a bacterial RNA polymerase and that includes a rifamycin fused ring system or a carboxyl of a sorangicin sidechain; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is —NH— or —S— and connects C3 of the rifamycin fused ring system or the carboxyl of a sorangicin sidechain to a residue corresponding in position to the acyl-Apa residue of GE23077.
2. The method of claim 1 , wherein X is a rifamycin or a rifamycin derivative that binds to the Rif target of a bacterial RNA polymerase; Y is a moiety that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker, wherein X is bonded to α through C3 of the rifamycin fused ring system, a moiety pendant from C3 of the rifamycin fused ring system, C4 of the rifamycin fused ring system, a moiety pendant from C4 of the rifamycin fused ring system, C11 of the rifamycin fused ring system, or a moiety pendant from C11 of the rifamycin fused ring system.
3. The method of claim 1 , wherein X is a sorangicin or a sorangicin derivative that binds to the Rif target of a bacterial RNA polymerase; Y is a moiety that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker.
4. The method of claim 1 , wherein X is a moiety that binds to the Rif target of a bacterial RNA polymerase; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker.
5. The method of claim 1 , wherein X is a moiety that binds to the Rif target of a bacterial RNA polymerase; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker, wherein Y is bonded to α through a residue corresponding in position to the acyl-Apa residue of GE23077 or the Ama residue of GE23077.
6. The method of claim 1 , wherein X is a moiety that binds to the Rif target of a bacterial RNA polymerase; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is a linker, wherein Y is bonded to α through a residue corresponding in position to the acyl-Apa residue of GE23077.
7. The method of claim 1 , wherein X is a moiety that binds to the Rif target of a bacterial RNA polymerase and is selected from the group consisting of rifamycin S, rifamycin SV, and sorangicin A; Y is GE23077; and α is a linker.
8. The method of claim 1 , wherein X is a moiety that binds to the Rif target of a bacterial RNA polymerase and that includes a rifamycin fused ring system or a carboxyl of a sorangicin sidechain; Y is GE23077 or a GE23077 derivative that binds to the GE23077 target of a bacterial RNA polymerase; and α is —NH— or —S— and connects C3 of the rifamycin fused ring system or the carboxyl of a sorangicin sidechain to a residue corresponding in position to the acyl-Apa residue of GE23077.