Bipartite inhibitors of bacterial RNA polymerase

1. A compound having a structural formula (I):

X-α-Y  (I)

wherein X is an moiety that binds to the Rif pocket of a bacterial RNA polymerase and is selected from the group consisting of a rifamycin derivative, Y is a moiety that binds to the secondary channel of a bacterial RNA polymerase and is selected from the group consisting of a lariat peptide, a derivative of a lariat-peptide, tagetitoxin or ppGpp, and α is a linker, wherein said linker has a length of from about 15 Å to about 35 Å.

2. A compound according to claim 1 , wherein said compound binds to a bacterial RNA polymerase.

3. A compound according to claim 2 , wherein said compound binds to a bacterial RNA polymerase with an affinity higher than that of X and Y separately.

4. A compound according to claim 2 , wherein said compound binds to a bacterial RNA polymerase resistant to at least one of X and Y.

5. A compound according to claim 1 , wherein said compound inhibits a bacterial RNA polymerase.

6. A compound according to claim 5 , wherein said compound inhibits a bacterial RNA polymerase with a potency higher than that of X and Y separately.

7. A compound according to claim 5 , wherein said compound inhibits a bacterial RNA polymerase resistant to at least one of X and Y.

8. A compound according to claim 1 , wherein X is a rifamycin derivative, and X is bonded to α through the rifamycin naphthol group.

9. A compound according to claim 8 , wherein X is a rifamycin derivative, and X is bonded to a through at least one of the rifamycin O12 atom, the rifamycin C3 atom, and the rifamycin C4 atom.

10. A compound according to claim 9 , wherein X is rifamycin SV, and X is bonded to a through the O12 atom of rifamycin SV.

11. A compound according to claim 1 wherein Y is a microcin J25 derivative.

12. A compound according to claim 1 , wherein Y is a microcin J25 derivative, and Y is bonded to X through a microcin J25 residue 5.

13. A compound according to claim 12 , wherein Y is a [Lys5]microcin J25, and Y is bonded to X through a Lys5 NZ atom of [Lys5]microcin J25.

14. A compound according to claim 1 , wherein α contains a covalent bond.

15. A compound according to claim 1 , wherein α contains a coordinate-covalent bond.

16. A compound according to claim 1 , wherein α contains a non-covalent bond.

17. A compound according to claim 1 , wherein said compound is prepared from precursors X-α′ and ′α-Y, wherein α′ and ′α are moieties that can react to form α.

18. A compound according to claim 17 , wherein said compound is prepared from precursors X-α′ and ′α-Y in the presence of a bacterial RNA polymerase.

19. A compound according to claim 17 , wherein said compound is prepared from precursors X-α′ and ′α-Y in the presence of a bacterial RNA polymerase, said bacterial RNA polymerase serving as a template for reaction of X-α′ and ′α-Y.

20. A compound according to claim 1 , having the general formula {rifamycin SV}-{CH 2 C(O)NH(CH 2 ) n NHC (O)CH 2 S (CH 2 ) 3 C(NH 2 + )}-{[Lys5]microcin J25}, where n is an integer from about 4 to about 18.

21. A compound according to claim 1 , having the general formula {rifamycin SV}-{CH 2 C(O)NH(CH 2 ) n NHC(O)CH 2 S(H 2 ) 3 C(NH 2 + )}-{[Lys5]microcin J25}, where n is an integer from about 6 to about 16.

22. A compound according to claim 21 , where n=12.

23. A compound according to claim 1 , having the general formula {rifamycin SV}-{CH 2 C(O)NH(CH 2 ) n NHC(O)(CH2) 2 (C 2 N 3 )(CH 2 ) 4 C(O)}-{[Lys5]microcin J25}, where n is an integer from about 2 to about 16.

24. A compound according to claim 1 , having the general formula {rifamycin SV}-{CH 2 C(O)NH(CH 2 ) n NHC(O)(CH2) 2 (C 2 N 3 )(CH 2 ) 4 C(O)}-{[Lys5]microcin J25}, where n is an integer from about 4 to about 14.

25. A compound according to claim 24 , where n=10.

26. A method of preparing a compound according to claim 1 , said method comprising:

providing precursors X-α′ and ′α-Y, and

reacting the α′ moiety of X-α′ and the ′α moiety of

′α-Y to form X-α-Y.

27. A method according to claim 26 , wherein one precursor contains an activated ester and the other precursor con ins an amine.

28. A method according to claim 26 , wherein one precursor contains a haloacetyl moiety and the other precursor contains an amine.

29. A method according to claim 26 , wherein one precursor contains a haloacetyl moiety and the other precursor contains a sulfhydryl.

30. A method according is claim 26 , wherein one precursor contains an azide and the other precursor contains an alkyne.

31. A method according to claim 26 , wherein one precursor contains an azide and the other precursor contains a phosphine.

32. A method according to claim 26 , wherein one precursor contains a boronic acid and the other precursor contains a substituted phenol.

33. A method according to claim 26 , wherein one precursor contains phenylboronic acid and the other precursor contains salicylhydroxamic acid.

34. A method according to claim 26 , wherein moieties .alpha.′ and ′.alpha, of precursors X-.alpha.′ and ′.alpha.-Y react in the presence of a bacterial RNA polymerase.

35. A method according to claim 34 , wherein the bacterial RNA polymerase serves as a template for reaction of X-.alpha.′ and ′.alpha.-Y.

36. A method of preparing a bipartite inhibitor of bacterial RNA polymerase, said method comprising reacting {rifamycin SV}-{CH 2 C(O)NH(CH 2 ) n NHC(O)CH 2 Z, where n is an integer from about 4 to about 18, and is a halogen, with HS(CH 2 ) 3 C(NH 2 + )}-{[Lys5]microcin J25}.

37. A method of using compound according to claim 1 to bind to a bacterial RNA polymerase.

38. A method of using compound according to claim 1 to inhibit a bacterial RNA polymerase.

39. A method of using compound according to claim 1 to inhibit bacterial gene expression.

40. A method of using the compound according to claim 1 to inhibit bacterial growth.

41. A method of using the compound according to claim 1 to treat bacterial infection.

42. A pharmaceutical preparation comprising a compound according to claim 1 and a physiologically acceptable carrier or excipient.