SEMISYNTHETIC GLYCOPEPTIDE ANTIBIOTICS DERIVED FROM LY264826 ACTIVE AGAINST VANCOMYCIN-RESISTANT ENTEROCOCCI

Certain derivatives of the glycopeptide antibiotic LY264826 with N-alk yl-linked substitutions on the epivancosamine sugar are active against glycopeptide-resistant enterococci, Six compounds representing our mo st active series were evaluated for activity against antibiotic-resist ant, gram-positive pathogens, For Enterococcus faecium and E. faecalis resistant to both vancomycin and teicoplanin, the MICs of the six sem isynthetic compounds for 90% of the strains tested were 1 to 4 mu g/ml , compared with 2,048 mu g/ml for vancomycin and 256 mu g/ml for LY264 826, For E. faecium and B. faecalis resistant to vancomycin but not te icoplanin, the MICs were 0.016 to 1 mu g/ml, compared with 64 to 1,024 mu g/ml for vancomycin. The compounds were highly active against vanc omycin-susceptible enterococci and against E. gallinarum and E. cassel iflavus and showed some activity against isolates of highly vancomycin -resistant leuconostocs and pediococci, The MICs for 90% of the strain s of methicillin-resistant Staphylococcus aureus tested were typically 0.25 to 1 mu g/ml, compared with 1 mu g/ml for vancomycin. Against me thicillin-resistant S. epidermidis, MICs ranged from 0.25 to 2 mu g/ml , compared with 1 to 4 mu g/ml for vancomycin and 4 to 16 mu g/ml for teicoplanin, The spectrum of these new compounds included activity aga inst teicoplanin-resistant, coagulase-negative staphylococci, The comp ounds exhibited exceptional potency against pathogenic streptococci, w ith MICs of less than or equal to 0.008 mu g/ml against Streptococcus pneumoniae, including penicillin-resistant isolates. In in vivo studie s with a mouse infection model, the median effective doses against a c hallenge by S. aureus, S. pneumoniae, or S. pyogenes were typically 4 to 20 times lower than those of vancomycin, Overall, these new glycope ptides, such as LY307599 and LY333328, show promise for use as agents against resistant enterococci, methicillin-resistant S. aureus, and pe nicillin-resistant pneumococci.