title: Substitution of amino acids 1 and 3 in teicoplanin aglycon: synthesis and antibacterial activity of three first non-natural dalbaheptides.
abstract: The replacement of amino acids 1 and 3 of glycopeptide antibiotics (dalbaheptides) 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 1 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-Lys1-Phe-3-TD-DHP-Me), MDL 64,945 (D-Lys1-Lys3-TD-DHP-Me), and MDL 64,468 (D-MeLeu1-Lys3-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 microgram/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.
authors.affiliation: Lepetit Research Center, Gerenzano (Varese), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Malabarba
authors.forename: R
authors.initials: R
authors.lastname: Ciabatti
authors.forename: E
authors.initials: E
authors.lastname: Gerli
authors.forename: F
authors.initials: F
authors.lastname: Ripamonti
authors.forename: P
authors.initials: P
authors.lastname: Ferrari
authors.forename: L
authors.initials: L
authors.lastname: Colombo
authors.forename: E N
authors.initials: EN
authors.lastname: Olsufyeva
authors.forename: A Y
authors.initials: AY
authors.lastname: Pavlov
authors.forename: M I
authors.initials: MI
authors.lastname: Reznikova
authors.forename: E I
authors.initials: EI
authors.lastname: Lazhko
authors.forename: M N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D006020:Glycopeptides; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides