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.

Mechanisms of daptomycin resistance in Staphylococcus aureus

“…LY264826 has the same peptide core structure as vancomycin but differs in the carbohydrate moieties present [37]. Oritavancin differs from LY264826 by the presence of an N-alkyl substitution on the epivancosamine sugar [2,38]. Perhaps this substitution allows oritavancin to evade the negative effect(s) of a putative cell surface structure alteration on its antistaphylococcal activity.…”

Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues

“…One of the most widely recognized peripheral modifications of glycopeptide antibiotics is the hydrophobic substitution of the vancosamine free amine first discovered at Eli Lilly and inspired by the lipophilic acyl groups found in teicoplanin. 190–192 To date, three semi-synthetic analogues; oritavancin ( 259 , 2014, The Medicines Company), 193 telavancin ( 260 , 2009, Theravance), 194,195 and dalbavancin ( 261 , 2014, Vicuron Pharmaceuticals Inc.) 196–198 that bear such substitution have been approved for clinical use (Figure 17). Importantly, the hydrophobic substituent enhances the antibiotic potency against both vancomycin sensitive and resistant pathogens.…”

Die Vancomycin-Antibiotica und der Kampf gegen resistente Bakterien

“…[78] Diese neue Verbindung weist eine bemerkenswerte Aktivität gegen VRE auf und ist in der Regel 50mal aktiver als Vancomycin. [79] In vitro ist sie auch etwa 4 ± 8mal aktiver gegen MRSA als Vancomycin, und ihre Wirksamkeit in vivo ist ähnlich hoch. [79] Bei Gruppo Lepetit-SpA erhielt man ebenfalls ein Glycopeptid mit vielversprechender In-vitro-und Invivo-Aktivität gegen vancomycinresistente Enterococcen.…”