Substitution of Amino Acids 1 and 3 in Teicoplanin Aglycon: Synthesis and Antibacterial Activity of Three First Non-natural Dalbaheptides

The replacement of amino acids I and 3 of glycopeptide antibiotics (dalbaheptidcs) with new amino acids or other chemical entities suitable to interact with both glycopeptide-resistant (D-Ala-D-Lactate) and susceptible (D-Ala-D-Ala) targets is one of the chemical strategies currently followed to pursue activity against highly glycopeptide-resistant VanA enterococci while maintaining activity against glycopeptide-susceptible Gram-positive bacteria, particularly methicillin-resistant staphylococci. As a preliminary approach, the substitution of amino acid I of deglucoteicoplanin (TD) with D-lysine or D-methylleucine and of its amino acid 3 with L-phenylalanine or L-lysine was investigated. In this paper, the synthesis and in vitro antibacterial activities of first non-natural dalbaheptide methyl ester aglycons MDL 63,166 (D-Lys 1 -Phe 3 -TD-DHP-Me), MDL 64,945 (D-Lys 1 -Lys 3 -TD-DHP-Me), and MDL 64,468 (D-MeLeu 1 -Lys 3 -TD-DHP-Me) are described. These compounds, which were obtained from intermediate TD-derived tetrapeptide methyl ester (TDTP-Me) according to a 9-step overall procedure, had excellent anti-staphylococcal activity. The most active derivative against staphylococci, MDL 64,945 (MIC: 0.063 μg/ml for S. aureus, S. epidermidis and S. haemolyticus) was inactive against VanA enterococci, while MDL 63,166 and MDL 64,468 were somewhat active against VanA strains of E. faecalis, MDL 64,468 was also moderately active against one VanA isolate of E. faecium and had marginal activity as TD against E. coli.