Vancomycin derivatives that inhibit peptidoglycan biosynthesis without binding D-Ala-D-Ala

Science

Volumn 284, Issue 5413, 1999, Pages 507-511

  Ge, Min ^a   Chen, Zhong ^a   Onishi, H Russell ^b   Kohler, Joyce ^b   Silver, Lynn L ^b   Kerns, Robert ^a   Fukuzawa, Seketsu ^a   Thompson, Christopher ^a   Kahne, Daniel ^a  

^a PRINCETON UNIVERSITY   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BAMBERMYCIN; CEFOXITIN; DEXTRO ALANINE; PEPTIDOGLYCAN; RAMOPLANIN; VANCOMYCIN DERIVATIVE;

ANTIBIOTIC RESISTANCE; ARTICLE; BACTERIAL CELL WALL; DRUG ACTIVITY; DRUG EFFICACY; DRUG STRUCTURE; GLYCOSYLATION; NONHUMAN; PEPTIDE SYNTHESIS; PRIORITY JOURNAL; PROTEIN BINDING; STRUCTURE ANALYSIS;

ANTI-BACTERIAL AGENTS; CARBOHYDRATES; CELL MEMBRANE; DIPEPTIDES; DRUG DESIGN; DRUG RESISTANCE, MICROBIAL; ENTEROCOCCUS FAECALIS; ESCHERICHIA COLI; GLYCOSYLATION; HEXOSYLTRANSFERASES; LIPID METABOLISM; MICROBIAL SENSITIVITY TESTS; PEPTIDOGLYCAN; PEPTIDOGLYCAN GLYCOSYLTRANSFERASE; PROTEIN BINDING; PROTEIN PRECURSORS; STRUCTURE-ACTIVITY RELATIONSHIP; VANCOMYCIN;

BACTERIA (MICROORGANISMS); POSIBACTERIA;

EID: 0033574743     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.284.5413.507     Document Type: Article

References (41)

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20. Many studies have used paniculate enzyme preparations to study the site of inhibition. However, the inhibitory activity of vancomycin in cells depends on the availability and distribution of various D-Ala-D-Ala binding sites on the cell surface. We use a permeabilized cell assay rather than a particulate enzyme assay so that both the enzymes and the cell wall precursors included in peptidoglycan synthesis are as dose to the native context as possible. For studies in which particulate enzyme preparations are used to evaluate the mechanism of action of vancomycin, see (3, 8, 17).
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32. C. Thompson, M. Ge, D. Kahne, J. Am. Chem. Soc. 121, 1237 (1999); Nicolaou's group has also reported chemical glycosytation of the vancomycin aglycon [K. C. Nicolaou et al., Angew. Chem. 111, 253 (1999)]. The vancomycin aglycon has been enzymatically glycosylated [P. J. Solenberg et al., Chem. Biol. 4, 195 (1997)].
33. C. Thompson, M. Ge, D. Kahne, J. Am. Chem. Soc. 121, 1237 (1999); Nicolaou's group has also reported chemical glycosytation of the vancomycin aglycon [K. C. Nicolaou et al., Angew. Chem. 111, 253 (1999)]. The vancomycin aglycon has been enzymatically glycosylated [P. J. Solenberg et al., Chem. Biol. 4, 195 (1997)].
34. C. Thompson, M. Ge, D. Kahne, J. Am. Chem. Soc. 121, 1237 (1999); Nicolaou's group has also reported chemical glycosytation of the vancomycin aglycon [K. C. Nicolaou et al., Angew. Chem. 111, 253 (1999)]. The vancomycin aglycon has been enzymatically glycosylated [P. J. Solenberg et al., Chem. Biol. 4, 195 (1997)].
35. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically (approved standard, NCCLS Document M7-A4, National Committee for Clinical Laboratory Standards, Wayne, PA, ed. 4, 1997).
36. 14C]GlcNAc (2 μCi/μmol) and ETB in a final volume of 0.1 ml. The reaction for the formation of uncross-linked peptidoglycan contained penicillin G (1 mg/ml). The reaction for the formation of cross-linked peptidoglycan lacked the penicillin. After incubating at 30°C for 30 min, 0.05 ml of 6 M pyridinium acetate (pH 4.2) and 0.2 ml of n-BuOH were added to terminate the reactions and to extract the bactoprenyl-linked intermediates. Phases were separated by centrifugation. The upper layer was isolated and the lower layer was reextracted with n-BuOH. The extracts were combined and back-extracted with 0.2 ml of distilled water. The radioactivity in a sample of trie n-BuOH phase was determined. The residue from the reaction run in the presence of penicillin G was resuspended in DMSO by sonication. The amount of immature peptidogtycan synthesized was determined by filtering the suspension through a hydrophilic Durapore PVDF (polyvinylidene difluoride) membrane filter (Millipore, 0.65 μm), washing the filter with 0.4 M ammonium acetate prepared in MeOH, and counting the radioactivity on the fitter. The residue from the reaction run without penicillin C was resuspended in 4% SDS and heated at 95°C for 15 min. The amount of cross-linked peptidoglycan synthesized was determined by filtering the hot-SDS-treated residue through a mixed cellulose membrane filter (0.45 μm; HAWP, Millipore), washing the filters with distilled water, and counting the radioactivity on the filter. The inhibition pattern was obtained by comparing the counts of different intermediates at various concentrations of the test compound to the counts obtained without the test compound.
37. The site of inhibition assay was developed by combining methods for analyzing individual steps and products involved in peptidoglycan biosynthesis [D. Mirelman, Y. Yashouv-Gan, U. Schwartz, Biochemistry 15, 1781 (1976); J. N. Umbreit and J. L. Strominger, J. Bacteriol. 112, 1306 (1972); Y. Van Heijenoort and J. Van Heijenoort, FEBS Lett. 110, 241 (1979); M. Di Berardino, A. Dijkstra, D. Stuber, W. Keck, M. Gubler, ibid. 392, 184 (1996)].
38. The site of inhibition assay was developed by combining methods for analyzing individual steps and products involved in peptidoglycan biosynthesis [D. Mirelman, Y. Yashouv-Gan, U. Schwartz, Biochemistry 15, 1781 (1976); J. N. Umbreit and J. L. Strominger, J. Bacteriol. 112, 1306 (1972); Y. Van Heijenoort and J. Van Heijenoort, FEBS Lett. 110, 241 (1979); M. Di Berardino, A. Dijkstra, D. Stuber, W. Keck, M. Gubler, ibid. 392, 184 (1996)].
39. The site of inhibition assay was developed by combining methods for analyzing individual steps and products involved in peptidoglycan biosynthesis [D. Mirelman, Y. Yashouv-Gan, U. Schwartz, Biochemistry 15, 1781 (1976); J. N. Umbreit and J. L. Strominger, J. Bacteriol. 112, 1306 (1972); Y. Van Heijenoort and J. Van Heijenoort, FEBS Lett. 110, 241 (1979); M. Di Berardino, A. Dijkstra, D. Stuber, W. Keck, M. Gubler, ibid. 392, 184 (1996)].
40. The site of inhibition assay was developed by combining methods for analyzing individual steps and products involved in peptidoglycan biosynthesis [D. Mirelman, Y. Yashouv-Gan, U. Schwartz, Biochemistry 15, 1781 (1976); J. N. Umbreit and J. L. Strominger, J. Bacteriol. 112, 1306 (1972); Y. Van Heijenoort and J. Van Heijenoort, FEBS Lett. 110, 241 (1979); M. Di Berardino, A. Dijkstra, D. Stuber, W. Keck, M. Gubler, ibid. 392, 184 (1996)].
41. Supported by Intercardia Research Laboratories, Merck Research Laboratories, The National Institutes of Health (National Research Service Award to R.K.), and the Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad (to S.F.).