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Journal Article

Semisynthetic glycopeptide antibiotics derived from LY264826 active against vancomycin-resistant enterococci.

T I Nicas, D L Mullen, J E Flokowitsch, D A Preston, N J Snyder, M J Zweifel, S C Wilkie, M J Rodriguez, R C Thompson, R D Cooper
T I Nicas
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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D L Mullen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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J E Flokowitsch
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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D A Preston
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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N J Snyder
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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M J Zweifel
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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S C Wilkie
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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M J Rodriguez
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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R C Thompson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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R D Cooper
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nicas_thalia_i@lilly.com
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DOI: 10.1128/AAC.40.9.2194
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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.

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Semisynthetic glycopeptide antibiotics derived from LY264826 active against vancomycin-resistant enterococci.
T I Nicas, D L Mullen, J E Flokowitsch, D A Preston, N J Snyder, M J Zweifel, S C Wilkie, M J Rodriguez, R C Thompson, R D Cooper
Antimicrobial Agents and Chemotherapy Sep 1996, 40 (9) 2194-2199; DOI: 10.1128/AAC.40.9.2194

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Semisynthetic glycopeptide antibiotics derived from LY264826 active against vancomycin-resistant enterococci.
T I Nicas, D L Mullen, J E Flokowitsch, D A Preston, N J Snyder, M J Zweifel, S C Wilkie, M J Rodriguez, R C Thompson, R D Cooper
Antimicrobial Agents and Chemotherapy Sep 1996, 40 (9) 2194-2199; DOI: 10.1128/AAC.40.9.2194
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