Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 Sep;40(9):2194–2199. doi: 10.1128/aac.40.9.2194

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

T I Nicas 1, D L Mullen 1, J E Flokowitsch 1, D A Preston 1, N J Snyder 1, M J Zweifel 1, S C Wilkie 1, M J Rodriguez 1, R C Thompson 1, R D Cooper 1
PMCID: PMC163498  PMID: 8878606

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.

Full Text

The Full Text of this article is available as a PDF (233.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arthur M., Molinas C., Depardieu F., Courvalin P. Characterization of Tn1546, a Tn3-related transposon conferring glycopeptide resistance by synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147. J Bacteriol. 1993 Jan;175(1):117–127. doi: 10.1128/jb.175.1.117-127.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beauregard D. A., Williams D. H., Gwynn M. N., Knowles D. J. Dimerization and membrane anchors in extracellular targeting of vancomycin group antibiotics. Antimicrob Agents Chemother. 1995 Mar;39(3):781–785. doi: 10.1128/AAC.39.3.781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bugg T. D., Dutka-Malen S., Arthur M., Courvalin P., Walsh C. T. Identification of vancomycin resistance protein VanA as a D-alanine:D-alanine ligase of altered substrate specificity. Biochemistry. 1991 Feb 26;30(8):2017–2021. doi: 10.1021/bi00222a002. [DOI] [PubMed] [Google Scholar]
  4. Cooper R. D., Snyder N. J., Zweifel M. J., Staszak M. A., Wilkie S. C., Nicas T. I., Mullen D. L., Butler T. F., Rodriguez M. J., Huff B. E. Reductive alkylation of glycopeptide antibiotics: synthesis and antibacterial activity. J Antibiot (Tokyo) 1996 Jun;49(6):575–581. doi: 10.7164/antibiotics.49.575. [DOI] [PubMed] [Google Scholar]
  5. Goldstein B. P., Candiani G., Arain T. M., Romanò G., Ciciliato I., Berti M., Abbondi M., Scotti R., Mainini M., Ripamonti F. Antimicrobial activity of MDL 63,246, a new semisynthetic glycopeptide antibiotic. Antimicrob Agents Chemother. 1995 Jul;39(7):1580–1588. doi: 10.1128/aac.39.7.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Handwerger S., Raucher B., Altarac D., Monka J., Marchione S., Singh K. V., Murray B. E., Wolff J., Walters B. Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin, and gentamicin. Clin Infect Dis. 1993 Jun;16(6):750–755. doi: 10.1093/clind/16.6.750. [DOI] [PubMed] [Google Scholar]
  7. Jett B., Free L., Sahm D. F. Factors influencing the vitek gram-positive susceptibility system's detection of vanB-encoded vancomycin resistance among enterococci. J Clin Microbiol. 1996 Mar;34(3):701–706. doi: 10.1128/jcm.34.3.701-706.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Johnson A. P., Uttley A. H., Woodford N., George R. C. Resistance to vancomycin and teicoplanin: an emerging clinical problem. Clin Microbiol Rev. 1990 Jul;3(3):280–291. doi: 10.1128/cmr.3.3.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jones R. N., Sader H. S., Erwin M. E., Anderson S. C. Emerging multiply resistant enterococci among clinical isolates. I. Prevalence data from 97 medical center surveillance study in the United States. Enterococcus Study Group. Diagn Microbiol Infect Dis. 1995 Feb;21(2):85–93. doi: 10.1016/0732-8893(94)00147-o. [DOI] [PubMed] [Google Scholar]
  10. Kenny M. T., Brackman M. A., Dulworth J. K. In vitro activity of the semisynthetic glycopeptide amide MDL 63,246. Antimicrob Agents Chemother. 1995 Jul;39(7):1589–1590. doi: 10.1128/aac.39.7.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Malabarba A., Ciabatti R., Scotti R., Goldstein B. P., Ferrari P., Kurz M., Andreini B. P., Denaro M. New semisynthetic glycopeptides MDL 63,246 and MDL 63,042, and other amide derivatives of antibiotic A-40,926 active against highly glycopeptide-resistant VanA enterococci. J Antibiot (Tokyo) 1995 Aug;48(8):869–883. doi: 10.7164/antibiotics.48.869. [DOI] [PubMed] [Google Scholar]
  12. Nagarajan R. Structure-activity relationships of vancomycin-type glycopeptide antibiotics. J Antibiot (Tokyo) 1993 Aug;46(8):1181–1195. doi: 10.7164/antibiotics.46.1181. [DOI] [PubMed] [Google Scholar]
  13. Nicas T. I., Mullen D. L., Flokowitsch J. E., Preston D. A., Snyder N. J., Stratford R. E., Cooper R. D. Activities of the semisynthetic glycopeptide LY191145 against vancomycin-resistant enterococci and other gram-positive bacteria. Antimicrob Agents Chemother. 1995 Nov;39(11):2585–2587. doi: 10.1128/aac.39.11.2585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Noble W. C., Virani Z., Cree R. G. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiol Lett. 1992 Jun 1;72(2):195–198. doi: 10.1016/0378-1097(92)90528-v. [DOI] [PubMed] [Google Scholar]
  15. Schwalbe R. S., Stapleton J. T., Gilligan P. H. Emergence of vancomycin resistance in coagulase-negative staphylococci. N Engl J Med. 1987 Apr 9;316(15):927–931. doi: 10.1056/NEJM198704093161507. [DOI] [PubMed] [Google Scholar]
  16. Shlaes D. M., Bouvet A., Devine C., Shlaes J. H., al-Obeid S., Williamson R. Inducible, transferable resistance to vancomycin in Enterococcus faecalis A256. Antimicrob Agents Chemother. 1989 Feb;33(2):198–203. doi: 10.1128/aac.33.2.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sturm A. W. Mobiluncus species and other anaerobic bacteria in non-puerperal breast abscesses. Eur J Clin Microbiol Infect Dis. 1989 Sep;8(9):789–792. doi: 10.1007/BF02185846. [DOI] [PubMed] [Google Scholar]
  18. Uttley A. H., Collins C. H., Naidoo J., George R. C. Vancomycin-resistant enterococci. Lancet. 1988 Jan 2;1(8575-6):57–58. doi: 10.1016/s0140-6736(88)91037-9. [DOI] [PubMed] [Google Scholar]
  19. Walsh C. T. Vancomycin resistance: decoding the molecular logic. Science. 1993 Jul 16;261(5119):308–309. doi: 10.1126/science.8392747. [DOI] [PubMed] [Google Scholar]
  20. Williams D. H., Waltho J. P. Molecular basis of the activity of antibiotics of the vancomycin group. Biochem Pharmacol. 1988 Jan 1;37(1):133–141. doi: 10.1016/0006-2952(88)90765-4. [DOI] [PubMed] [Google Scholar]
  21. Woodford N., Johnson A. P., Morrison D., Speller D. C. Current perspectives on glycopeptide resistance. Clin Microbiol Rev. 1995 Oct;8(4):585–615. doi: 10.1128/cmr.8.4.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. al-Obeid S., Gutmann L., Shlaes D. M., Williamson R., Collatz E. Comparison of vancomycin-inducible proteins from four strains of Enterococci. FEMS Microbiol Lett. 1990 Jun 15;58(1):101–105. doi: 10.1016/0378-1097(90)90110-c. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES