GLYCOPEPTIDE ANTIBIOTIC ANALOGS EFFECTIVE AGAINST VANCOMYCIN-RESISTANT BACTERIAL STRAINS

摘要

The invention is directed to glycopeptide antibiotics and their aglycones that are engineered to overcome bacterial resistance by replacement of a single, specific peptide carboxamide group in the core peptide of the glycopeptide antibiotic with an amidine group. The amidine pseudopeptide analog of the glycopeptide is effective in killing vancomycin-resistant bacteria at therapeutically achievable concentrations in a patient. For example, a [ψ[C(═NH)NH]Tpg4]- vancomycin aglycon designed to exhabit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria has been shown to overcome a common mode of bacterial resistance to the “last resort” antibiotics of the glycopeptide class. The pseudopeptide amidine analogs can be prepared from corresponding pseudopeptide thioamide analogs, which can be prepared synthetically, semi-synthetically, or biosynthetically.

主权项

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a carboxamide O atom of a D ring-bearing aminoacid residue of the peptide core of the glycopeptide or aglycone has been replaced by an NH group, to provide a respective ψ-amidine pseudopeptide analog of the glycopeptide antibiotic or aglycone.