title: Semisynthetic glycopeptide antibiotics derived from LY264826 active against vancomycin-resistant enterococci.
abstract: Certain derivatives of the glycopeptide antibiotic LY264826 with N-alkyl-linked substitutions on the epivancosamine sugar are active against glycopeptide-resistant enterococci. Six compounds representing our most active series were evaluated for activity against antibiotic-resistant, gram-positive pathogens. For Enterococcus faecium and E. faecalis resistant to both vancomycin and teicoplanin, the MICs of the six semisynthetic compounds for 90% of the strains tested were 1 to 4 micrograms/ml, compared with 2,048 micrograms/ml for vancomycin and 256 micrograms/ml for LY264826. For E. faecium and E. faecalis resistant to vancomycin but not teicoplanin, the MICs were 0.016 to 1 micrograms/ml, compared with 64 to 1,024 micrograms/ml for vancomycin. The compounds were highly active against vancomycin-susceptible enterococci and against E. gallinarum and E. casseliflavus and showed some activity against isolates of highly vancomycin-resistant leuconostocs and pediococci. The MICs for 90% of the strains of methicillin-resistant Staphylococcus aureus tested were typically 0.25 to 1 micrograms/ml, compared with 1 microgram/ml for vancomycin. Against methicillin-resistant S. epidermidis MICs ranged from 0.25 to 2 micrograms/ml, compared with 1 to 4 micrograms/ml for vancomycin and 4 to 16 micrograms/ml for teicoplanin. The spectrum of these new compounds included activity against teicoplanin-resistant, coagulase-negative staphylococci. The compounds exhibited exceptional potency against pathogenic streptococci, with MICs of < or = 0.008 microgram/ml against Streptococcus pneumoniae, including penicillin-resistant isolates. In in vivo studies with a mouse infection model, the median effective doses against a challenge by S. aureus, S. pneumoniae, or S. pyogenes were typically 4 to 20 times lower than those of vancomycin. Overall, these new glycopeptides, such as LY307599 and LY333328, show promise for use as agents against resistant enterococci, methicillin-resistant S. aureus, and penicillin-resistant pneumococci.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
authors.forename: T I
authors.initials: TI
authors.lastname: Nicas
authors.forename: D L
authors.initials: DL
authors.lastname: Mullen
authors.forename: J E
authors.initials: JE
authors.lastname: Flokowitsch
authors.forename: D A
authors.initials: DA
authors.lastname: Preston
authors.forename: N J
authors.initials: NJ
authors.lastname: Snyder
authors.forename: M J
authors.initials: MJ
authors.lastname: Zweifel
authors.forename: S C
authors.initials: SC
authors.lastname: Wilkie
authors.forename: M J
authors.initials: MJ
authors.lastname: Rodriguez
authors.forename: R C
authors.initials: RC
authors.lastname: Thompson
authors.forename: R D
authors.initials: RD
authors.lastname: Cooper
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D016983:Enterococcus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D013290:Streptococcal Infections / Q000382:microbiology / Q000517:prevention & control; D014640:Vancomycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; C057893:chloroorienticin A; D014640:Vancomycin