Glycopeptide antibiotic analogs effective against vancomycin-resistant bacterial strains

1. An antibiotic glycopeptide-analogous compound for treatment of glycopeptide-resistant bacterial infections, comprising a pseudopeptide analog of a glycopeptide antibiotic or aglycone thereof, wherein the compound comprises a core pseudopeptide sequence having an amidine group that replaces a carboxamide linking group of a core peptide of the glycopeptide antibiotic or aglycone thereof, wherein a carboxamide O atom of a D ring-bearing amino acid residue of the peptide core of the glycopeptide or aglycone has been replaced by an NH group, to provide a respective Ψ-amidine pseudopeptide analog of the glycopeptide antibiotic or aglycone.

2. The compound of claim 1 , wherein the core peptide sequence of the glycopeptide or aglycone thereof is recited N-terminal to C-terminal aa-Phe′-aa-Phgly′-Phgly′-Phe′-Phgly′, wherein aa signifies an amino acid residue, and Phe′ and Phgly′ signify modified phenylalanine and modified phenylglycine amino acid residues respectively; wherein the carboxamide group that is replaced by the amidine group is disposed at the fourth peptide bond from the N-terminal aa group.

3. The compound of claim 2 , wherein the core peptide sequence is recited N-terminal to C-terminal aa-Phe′-Phgly′-Phgly′-Phgly′-Phe′-Phgly′, wherein aa signifies an amino acid residue, and Phe′ and Phgly′ respectively signify modified phenylalanine and modified phenylglycine amino acid residues respectively; wherein the carboxamide group that is replaced by the amidine group is disposed at the fourth peptide bond from the N-terminal aa group.

4. The compound of claim 1 , wherein the amino acid residue bearing the D ring is a Phgly′ amino acid residue additionally coupled via aryl ether bonds to a C-ring of a Phe′ amino acid residue and to an E-ring of a Phe′ amino acid residue, wherein Phe′ and Phgly′ respectively signify modified phenylalanine and modified phenylglycine amino acid residues, respectively.

5. The compound of claim 1 , wherein the D ring amino acid residue pseudopeptide amidine bond NH group, when complexed with a peptidoglycan bacterial cell wall precursor or model thereof comprising a D-Ala-D-Ala C-terminal dipeptide domain is hydrogen bonded in the complex to a peptide nitrogen atom of the D-Ala-D-Ala peptide bond.

6. The compound of claim 1 , wherein the antibiotic glycopeptide-analogous compound is vancomycin, teicoplanin, balhimycin, actinoidin, or ristomycin.

7. The compound of claim 1 for treatment of infections caused by vancomycin-resistant bacteria, wherein the compound is any one of the following vancomycin-analogous [Ψ[C(═NH)NH]Tpg 4 ]-amidine analogs:

or wherein the compound is any one of the following vancomycin aglycone [Ψ[C(═NH)NH]Tpg 4 ]-amidine analogs:

or any pharmaceutically acceptable salt thereof;

or any combination thereof.

8. A glycopeptide-analogous compound for use as a precursor in preparation of an antibiotic of claim 1 for treatment of glycopeptide-resistant bacterial infections, comprising a pseudopeptide analog of a glycopeptide antibiotic or aglycone thereof, wherein the compound comprises a core pseudopeptide sequence having an thioamide group that replaces a carboxamide linking group of a core peptide of the glycopeptide antibiotic or aglycone thereof, wherein a carboxamide 0 atom of a D ring-bearing aminoacid residue of the peptide core of the glycopeptide or aglycone is replaced by an S atom, to provide a respective Ψ-thioamide pseudopeptide analog of the glycopeptide antibiotic or aglycone.

9. The compound of claim 8 , wherein the core peptide sequence of the glycopeptide or aglycone thereof is recited N-terminal to C-terminal aa-Phe′-aa-Phgly′-Phgly′-Phe′-Phgly′, wherein aa signifies an amino acid residue, and Phe′ and Phgly′ signify modified phenylalanine and modified phenylglycine amino acid residues respectively; wherein the carboxamide group that is replaced by the thioamide group is disposed at the fourth peptide bond from the N-terminal aa group.

10. The compound of claim 9 , wherein the core peptide sequence is recited N-terminal to C-terminal aa-Phe′-Phgly′-Phgly′-Phgly′-Phe′-Phgly′, wherein aa signifies an amino acid residue, and Phe′ and Phgly′ respectively signify modified phenylalanine and modified phenylglycine amino acid residues respectively; wherein the carboxamide group that is replaced by the thioamide group is disposed at the fourth peptide bond from the N-terminal aa group.

11. The compound of claim 8 , wherein the compound is a vancomycin [Ψ[C(═S)NH]Tpg 4 ]-thioamide analog of formula

or wherein the compound is a vancomycin aglycone [Ψ[C(═S)NH]Tpg 4 ]-thioamide analog of formula

12. The compound of claim 1 , comprising a [Ψ[C(═NH)NH]Tpg 4 ]-analog of vancomycin or an aglycone thereof of formula (V)

wherein

R 1 is H, or a glycosyl moiety;

R 2 is CO 2 R, CH 2 OR, or CONR 2 , wherein R is H or (C 1 -C 6 )alkyl;

R 3 is an aminoacyl group, optionally N-alkylated;

R 4 at each occurrence is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, a glycosyl moiety;

R 5 is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkanoyl;

R 6 is group of formula, (CR 2 )—R 6A wherein R 6A is aryl, CO 2 R, CONR 2 , (C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkanoyl;

R 7 at each occurrence is independently H, or a glycosyl moiety;

or a pharmaceutically acceptable salt thereof;

or a mixture thereof.

13. The compound of claim 12 wherein the glycosyl moiety of R 1 is of formula

wherein R 8 is alkyl, aryl, heterocyclyl, heteroaryl; a wavy line indicates a point of bonding;

or an epimer thereof or deoxy analog thereof.

14. A method of preparing the antibiotic glycopeptide-analogous amidine compound of claim 1 , comprising contacting the glycopeptide-analogous thioamide compound and ammonia, in the presence of a silver ion, optionally in a solvent.

15. The method of claim 14 wherein, the silver ion is provided by any one of silver acetate, silver triflate, silver tetrafluoborate, silver trifluoroacetate, or silver antimonyhexafluoride, or any combination thereof; or wherein the contacting is in a solvent comprising water or alcohol, or both; or wherein the contacting is at about 25° C.; or any combination thereof.

16. The method of claim 14 , wherein the thioamide compound is derived from a fermentation process.

17. The method of claim 14 comprising preparing a vancomycin [Ψ[C(═NH)NH]Tpg 4 ]-amidine analog of formula (IA)

or of formula (IB)

or of formula (IC)

by contacting a vancomycin [Ψ[C(═S)NH]Tpg 4 ]-thioamide analog of formula (IIIA)

or of formula (IIIB)

or of formula (IIIC)

respectively,

or comprising preparing a vancomycin aglycone [Ψ[C(═NH)NH]Tpg 4 ]-amidine analog of formula (IIA)

or of formula (IIB)

or of formula (IIC)

by contacting a vancomycin [Ψ[C(═S)NH]Tpg 4 ]-thioamide analog of formula (IVA)

or of formula (IVB)

or of formula (IVC)

respectively,

and a solution of a silver salt and ammonia in an alcoholic solvent, to provide the respective vancomycin amidine analog or vancomycin amidine aglycone analog, respectively.

18. A method of killing a vancomycin-resistant bacterial strain, comprising contacting the bacteria with an effective amount or concentration of an antibiotic compound of claim 1 .

19. A method of treating an infection in a patient caused by a bacterial population comprising a vancomycin-resistant bacterial strain, comprising administering to the patient an effective amount of an antibiotic compound of claim 1 .

20. A compound of formula