Novel Glycopeptide Antibiotics: N-Alkylated Derivatives Active Against Vancomycin-Resistant Enterococci.

Rodriguez, Michael J.; Snyder, Nancy; Zweifel, Mark J.; Wilkie, Stephen C.; Stack, Douglas R.; Cooper, R. D. G.; Nicas, Thalia I.; Mullen, D. L.; Butler, Thomas F.; Thompson, Richard C.

doi:10.7164/antibiotics.51.560

Cited by 52 publications

(64 citation statements)

References 9 publications

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“…Nevertheless, substantive differences are present between what we will call the final or "modified" [ 19 F] oritavancin model (Figures 15-16, top) and the MD model (30) of Cegelski et al (Figures 15-16, bottom). The differences are: (i) the pentaglycyl bridge in the modified model is helical, consistent with the reported glycyl carbonyl-carbon chemical shifts (15) and pentaglycyl endto-end distance (20); (ii) the pentaglycyl bridging segment is lowered into a protective cleft formed by the 4-epi-vancosamine and the glycopeptide core so that it will be in position to account for the 13 Figures 8 and 11); (iii) the D-iso-Gln of the bound stem is moved up towards the 4-epi-vancosamine moiety; and (iv) the unbound neighboring stem is moved away from the C-terminus of the glycopeptide core and proximity to the bound stem. In the discussion of other structural modifications that follows, reference to the [ 19 F]oritavancin-PG model will always be to the "modified" model of Figures 15-16 (top).…”

Section: Discussion Models For [ 19 F]oritavancin Complexessupporting

confidence: 67%

“…The 13 Figure 9, and a total dephasing after 30 msec of 7.3%. These arrangements provided the best match between calculated and observed dephasing and placed the 19 F of both glycopeptides approximately 6 Å from the nearest glycyl carbonyl carbon, and 11 Å from the farthest, at either end of the helical bridge.…”

Section: Lcta Complexes With [1-13 C]glycine Labeled Whole Cellsmentioning

confidence: 97%

“…aureus cells were grown in 300 ml of defined media (20) containing [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glycine and L-[ε -15 N]lysine. The cells were harvested at OD 660 = 1.0 and were complexed with 6.7 mg (4.0 μmoles) of FPBV, resulting in 66% cell-wall binding-site occupancy (15).…”

Section: Growth Of Cells and Formation Of Complexesmentioning

confidence: 99%

“…Radio frequency pulses for 13 C and 15 N were produced by 1-kW ENI (Andover, MA) LPI-10 power amplifiers. Radio frequency pulses for 1 H were produced by a 1-kW Kalmus Engineering Int.…”

Section: Rotational-echo Double Resonancementioning

confidence: 99%

“…Natural-abundance 13 C peptidoglycan peaks appear between 20 and 60 ppm in the full-echo spectrum ( Figure 5, bottom). Some of the [1-13 C]glycine was used for biosynthesis of purines (149 ppm).…”

Section: Fpbv Complex With [1-13 C]gly-labeled Whole Cellsmentioning

confidence: 99%

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Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by ¹³C{¹⁹F} and ¹⁵N{¹⁹F} Rotational-Echo Double Resonance

et al. 2006

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Solid-state NMR has been used to examine isolated cell walls and intact whole cells of Staphylococcus aureus complexed to 5 different vancomycin, eremomycin, and chloroeremomycin derivatives. The cell walls and whole cells were specifically labeled with D-[1-13 C]alanine, or a combination of [1-13 C]glycine and [ε-15 N]lysine. Each of the bound glycopeptides had a 19 F-labeled substituent at either its C-terminus or disaccharide position. The 13 C{ 19 F} rotational-echo doubleresonance (REDOR) dephasing for the cell-wall 13 C-labeled bridging pentaglycyl segment connecting a glycopeptide-complexed peptidoglycan stem with its neighboring stem indicates that the fluorine labels for all bound glycopeptides are positioned at one end or the other of the bridge. An exception is N'-(p-trifluoromethoxybenzyl)chloroeremomycin whose hydrophobic substituent differs in length by one phenyl group compared to that of oritavancin, N'-4- [(4-chlorophenyl) benzyl)]chloroeremomycin. For this drug the fluorine label is near the middle of the pentaglycyl segment. The 15 N{ 19 F} REDOR dephasing shows proximity of the fluorine to the bridge-link site of the pentaglycyl bridge for C-terminus-substituted moieties, and to the cross-link site for disaccharide-substituted moieties. Full-echo REDOR spectra of cell-wall complexes from cells labeled by D-[1-13 C]alanine (in the presence of an alanine racemase inhibitor) reveal three different carbonyl-carbon chemical-shift environments, arising from the D-Ala-D-Ala binding site and the DAla-Gly-1 cross-link site. The REDOR results indicate a single fluorine dephasing center in each peptidoglycan complex. Molecular models of the mature cell-wall complexes that are consistent with internuclear distances obtained from 13 C{ 19 F} and 15 N{ 19 F} REDOR dephasing allow a correlation of structure and antimicrobial activity of the glycopeptides. KeywordsDipolar coupling; glycopeptide antibiotic; magic-angle spinning; peptidoglycan; solid-state NMR; transglycosylase Vancomycin is a potent antibiotic that is effective against multi-drug-resistant Gram-positive bacteria including methicillin-resistant S. aureus. As many as 60% of clinically isolated strains of S. aureus are methicillin resistant (1), which means that vancomycin is one of the most important antibiotics in use today. Vancomycin inhibits the transglycosylation step in the † This paper is based on work supported by the National Institutes of Health under grant number EB02058. * Jacob Schaefer, NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 August 9. The emergence of vancomycin-resistant enterococci (VRE) has limited vancomycin usage against methicillin-resistant S. aureus. In 2002, vancomycin-resistant S. aureus (VRSA) with a minimum inhibitory concentration (MIC) of greater than 128 μg/mL was recovered from a patient in Michigan who was being treated with multiple antibiotics (5). E. faecalis, a vancomycin-resistant enterococcus, was also recovered from the patient. The VRSA isolat...

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Section: Discussion Models For [ 19 F]oritavancin Complexessupporting

confidence: 67%

Section: Lcta Complexes With [1-13 C]glycine Labeled Whole Cellsmentioning

confidence: 97%

Section: Growth Of Cells and Formation Of Complexesmentioning

confidence: 99%

“…Radio frequency pulses for 13 C and 15 N were produced by 1-kW ENI (Andover, MA) LPI-10 power amplifiers. Radio frequency pulses for 1 H were produced by a 1-kW Kalmus Engineering Int.…”

Section: Rotational-echo Double Resonancementioning

confidence: 99%

Section: Fpbv Complex With [1-13 C]gly-labeled Whole Cellsmentioning

confidence: 99%

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Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by ¹³C{¹⁹F} and ¹⁵N{¹⁹F} Rotational-Echo Double Resonance

et al. 2006

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Chemie, Biologie und medizinische Anwendungen der Glycopeptid-Antibiotika

Nicolaou

Boddy

Bräse³

et al. 1999

Angewandte Chemie

166

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Der Krieg gegen pathogene Bakterien ist noch nicht vorbei! Zwar bilden Vancomycin und andere Glycopeptid‐Antibiotika eine letzte Verteidigungslinie gegen zahlreiche mehrfachresistente Bakterien, doch ihr leichtfertiger Gebrauch hat zur Bildung etlicher gefährlicherer Bakterienstämme geführt. Das Verständnis der chemischen und biologischen Eigenschaften dieser hochkomplexen Glycopeptide dürfte eine entscheidende Rolle für die Entdeckung und Entwicklung neuer Antibiotika spielen.

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Kohlenhydrate in der Antibiotikaforschung: ein neuer Ansatz zur Resistenzbekämpfung

Ritter

Wong

2001

Angew. Chem.

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Novel Glycopeptide Antibiotics: N-Alkylated Derivatives Active Against Vancomycin-Resistant Enterococci.

Cited by 52 publications

References 9 publications

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by ¹³C{¹⁹F} and ¹⁵N{¹⁹F} Rotational-Echo Double Resonance

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by ¹³C{¹⁹F} and ¹⁵N{¹⁹F} Rotational-Echo Double Resonance

Chemie, Biologie und medizinische Anwendungen der Glycopeptid-Antibiotika

Kohlenhydrate in der Antibiotikaforschung: ein neuer Ansatz zur Resistenzbekämpfung

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Novel Glycopeptide Antibiotics: N-Alkylated Derivatives Active Against Vancomycin-Resistant Enterococci.

Cited by 52 publications

References 9 publications

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by 13C{19F} and 15N{19F} Rotational-Echo Double Resonance

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by 13C{19F} and 15N{19F} Rotational-Echo Double Resonance

Chemie, Biologie und medizinische Anwendungen der Glycopeptid-Antibiotika

Kohlenhydrate in der Antibiotikaforschung: ein neuer Ansatz zur Resistenzbekämpfung

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Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by ¹³C{¹⁹F} and ¹⁵N{¹⁹F} Rotational-Echo Double Resonance

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by ¹³C{¹⁹F} and ¹⁵N{¹⁹F} Rotational-Echo Double Resonance