New derivatives of eremomycin containing 15N or F atoms for NMR study

Solov’eva, S. E.; Printsevskaya, Svetlana S.; Olsuf'eva, E. N.; Batta, Gyula; Preobrazhenskaya, M. N.

doi:10.1134/s1068162008060162

Cited by 5 publications

(7 citation statements)

References 12 publications

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“…17 The [ 15 N]ammonium chloride was used to incorporate 15 N-enriched labels at the amino acid positions 3 and 7 of carboxyeremomycin using PyBOP and HBPyU as condensing reagents. 25 The MS-ESI calculated mass for LCTA-1421 (C 73 H 90 N 9 15 N 2 O 25 Cl) [M+H] + was 1557.57, and the found [M+2H] 2+ mass was 779.80. The chemical shift of the 15 N-amide at the C-terminus (amino acid position 7) was 110.22 ppm, and the 15 N-amide side chain of asparagine (amino acid position 3) was 113.28 ppm by solution-state NMR.…”

Section: Methodsmentioning

confidence: 99%

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The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem

et al. 2016

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Glycopeptide antibiotics inhibit cell wall biosynthesis in Gram-positive bacteria by targeting the peptidoglycan (PG) pentapeptide stem structure (L-Ala-D-iso-Gln-L-Lys-D-Ala-D-Ala). Structures of glycopeptide complexed with PG-stem mimic have shown that the D-Ala-D-Ala is the primary drug-binding site; however, biochemical evidences suggest that the glycopeptide-PG interaction involves more than D-Ala-D-Ala binding. Glycopeptide interactions with the non-D-Ala-D-Ala segment of the PG stem were investigated using solid-state NMR. LCTA-1421, a double 15N-enriched eremomycin derivative with a C-terminus 15N-amide and 15N-Asn amide, was complexed with whole cells of Staphylococcus aureus grown in a defined media containing L-[3-13C]Ala and D-[1-13C]Ala in the presence of alanine racemase inhibitor alaphosphin. 13C{15N} and 15N{13C} rotational-echo double resonance (REDOR) NMR measurements determined the 13C-15N internuclear distances between the 15N-Asn amide of LCTA-1421 and the 13Cs of the bound D-[1-13C]Ala-D-[1-13C]Ala to 5.1 and 4.8 Å, respectively. These measurements also determined the distance from the C-terminus 15N-amide of LCTA-1421 to the L-[3-13C]Ala of PG to 3.5 Å. The measured REDOR distance constraints position the glycopeptide C-terminus in proximity to the L-Ala of the PG, suggesting that the C-terminus of glycopeptide interacts near the L-Ala segment of the PG stem. In vivo REDOR measurements provided structural insight into how C-terminus modified glycopeptide antibiotics operate.

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Section: Methodsmentioning

confidence: 99%

“…Synthesis of LCTA-1421 and LCTA-1110. The synthesis of bis[ 15 N]amide-carboxyeremomycin (LCTA-1421) was described by Solov'eva et al 25 Briefly, eremomycin was treated with barium hydroxide at 37 °C for 4 h to yield carboxyeremomycin. 17 Growth of Whole Cells of S. aureus.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem

et al. 2016

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“…Adjacent parallel stems offer the same binding site for eremomycin analogues (14) in FemA (Figure 7) as in the parent strain of S. aureus (2). FemA has a mixture of parallel and perpendicular stems but LCTA-1110 prefers the parallel-stem sites (Figure 7, left).…”

Section: Resultsmentioning

confidence: 99%

REDOR constraints on the peptidoglycan lattice architecture of Staphylococcus aureus and its FemA mutant

Singh¹,

Kim²,

Sharif³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The peptidoglycan of Gram-positive bacteria consists of glycan chains with attached short peptide stems cross-linked to one another by glycyl bridges. The bridge of Staphylococcus aureus has five glycyl units and that of its FemA mutant has one. These long- and short-bridge cross-links create totally different cell-wall architectures. S. aureus and its FemA mutant grown in the presence of an alanine-racemase inhibitor were labeled with D-[1-13C]alanine, L-[3-13C]alanine, [2-13C]glycine, and L-[5-19F]lysine to characterize some details of the peptidoglycan tertiary structure. Rotational-echo double-resonance (REDOR) NMR of isolated cell walls was used to measure internuclear distances between 13C-labeled alanines and 19F-labeled lysine incorporated in the peptidoglycan. The alanyl 13C labels in the parent strain were preselected for C{F} and C{P} REDOR measurement by their proximity to the glycine label using 13C-13C spin diffusion. The observed 13C-13C and 13C-31P distances are consistent with a tightly packed architecture containing only parallel stems in a repeating structural motif within the peptidoglycan. Dante selection of D-alanine and L-alanine frequencies followed by 13C-13C spin diffusion rules out scrambling of carbon labels. Cell walls of FemA were also labeled by a combination of D-[1-13C]alanine and L-[15N]alanine. Proximity of chains was measured by C{N} and N{C} REDOR distances and asymptotic plateaus, and both were consistent with a mixed-geometry model. Binding of an 19F-labeled eremomycin analogue in the FemA cell wall matches that of binding to the parent-strain cell wall and reveals the proximity of parallel stems in the alternating parallel-perpendicular mixed-geometry model for the FemA peptidoglycan lattice.

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“…Semisynthetic derivatives 3–6 were synthesized from vancomycin (1) or eremomycin (2) by previously described methods 23 – 25 , 31 – 33 for glycopeptide carboxamides ( Figure 1 ). Compounds 3–6 were synthesized by condensation of 1 or 2 (1 eq.)…”

Section: Methodsmentioning

confidence: 99%

“…Another promising semisynthetic derivative of eremomycin amide was active against vancomycin-susceptible staphylococci and enterococci, as well as against VISA (MIC =0.5–0.25 mg/L). 33 In the rotational-echo double solid state nuclear magnetic resonance experiments with a labeled analog (Kim et al) was also shown that this compound has an additional binding site to the main site- d -Ala- d -Ala with fragments of the structure of cell-wall peptidoglycan of S. aureus . 34 , 35 Like several semisynthetic eremomycin derivatives modified at the C-terminus of the peptide core, eremomycin amides exhibited less pronounced pseudoallergic reactions compared with the parent antibiotic 2 in animal tests.…”

Section: Introductionmentioning

confidence: 97%

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

Olsufyeva¹,

Shchekotikhin²,

Bychkova³

et al. 2018

DDDT

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PurposeDevelopment of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions.MethodsSemisynthetic glycopeptides 3–6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitory concentration (MIC) for the new derivatives was measured by the broth micro-dilution method on a panel of clinical isolates of Staphylococcus and Enterococcus. Acute toxicity (50% lethal dose, maximum tolerated doses), antibacterial efficacy on model of systemic bacterial infection with S. aureus and pseudoallergic inflammatory reaction (on concanavalin A) of eremomycin pyrrolidide (5) were evaluated in mice according to standard procedures.ResultsThe eremomycin pyrrolidide (5) was the most active compound and showed a high activity against Gram-positive bacteria: vancomycin-susceptible staphylococci and enterococci (minimum inhibitory concentrations [MICs] 0.13–0.25 mg/L), as well as vancomycin-intermediate resistant Staphylococcus aureus (MICs 1 mg/L). Antimicrobial susceptibility tested on a panel of 676 isolates showed that 5 had similar activity for the genera Staphylococcus and Enterococcus with MIC90=0.5 mg/L, while vancomycin had MIC90=1–2 mg/L. The number of resistant strains of Enterococcus faecium (vancomycin-resistant enterococci) (MIC =64 mg/L) with this value was 7 (8%) for vancomycin (1) and 0 for the compound 5. In vivo comparative studies in a mouse model of systemic bacterial infection with S. aureus demonstrated that the efficacy of 5 was notably higher than that of the original antibiotics 1 and 2. In contrast to 1, compound 5 did not induce pseudoallergic inflammatory reaction (on concanavalin A).ConclusionThe new semisynthetic derivative eremomycin pyrrolidide (5) has high activity against staphylococci and enterococci including vancomycin-resistant strains. Compound 5 has a higher efficacy in a model of staphylococcal sepsis than vancomycin (1) or eremomycin (2). In striking contrast to natural antibiotics, the novel derivative 5 does not induce a pseudoallergic inflammatory reaction to concanavalin A and therefore has no histamine release activity. These results indicate the advantages of a new semisynthetic glycopeptide antibiotic eremomycin pyrrolidide (5) which may be a prospective antimicrobial agent for further pre-clinical and clinical evaluations.

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New derivatives of eremomycin containing 15N or F atoms for NMR study

Cited by 5 publications

References 12 publications

The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem

The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem

REDOR constraints on the peptidoglycan lattice architecture of Staphylococcus aureus and its FemA mutant

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

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