SUBSTITUTION OF AMINO-ACID-1 AND AMINO-ACID-3 IN TEICOPLANIN AGLYCON - SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF 3 FIRST NONNATURAL DALBAHEPTIDES

The replacement of amino acids 1 and 3 of glycopeptide antibiotics (da lbaheptides) with new amino acids or other chemical entities suitable to interact with both glycopeptide-resistant (D-Ala-D-Lactate) and sus ceptible (D-Ala-D-Ala) targets is one of the chemical strategies curre ntly followed to pursue activity against highly glycopeptide-resistant VanA enterococci while maintaining activity against glycopeptide-susc eptible Gram-positive bacteria, particularly methicillin-resistant sta phylococci. As a preliminary approach, the substitution of amino acid of deglucoteicoplanin (TD) with D-lysine or D-methylleucine and of its amino acid 3 with L-phenylalanine or L-lysine was investigated. In th is paper, the synthesis and in vitro antibacterial activities of first non-natural dalbaheptide methyl ester aglycons MDL 63,166 (D-Lys(1)-P he(3)-TD-DHP-Me), MDL 64,945 (D-Lys(1)-Lys(3)-TD-DHP-Me), and MDL 64,4 68 (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 staphyloco cci, MDL 64,945 (MIG: 0.063 mu g/ml for S. aureus, S. epidermidis and S. haemolyticus) was inactive against VanA enterococci, while MDL 63,1 66 and MDL 64,468 were somewhat active against VanA strains of E. faec alis; MDL 64,468 was also moderately active against one VanA isolate o f E. faecium and had marginal activity as TD against E. coli.