Synthesis of Tridecaptin–Antibiotic Conjugates with in Vivo Activity against Gram-Negative Bacteria

A series
of tridecaptin–antibiotic conjugates were synthesized
and evaluated for in vitro and in vivo activity against Gram-negative
bacteria. Covalently linking unacylated tridecaptin A1 (H-TriA1) to rifampicin, vancomycin, and erythromycin enhanced their
activity in vitro but not by the same magnitude as coadministration
of the peptide and these antibiotics. The antimicrobial activities
of the conjugates were retained in vivo, with the H-TriA1-erythromycin conjugate proving a more effective treatment of Klebseilla pneumoniae infections in mice than erythromycin
alone or in combination with H-TriA1.