Importance of the Structure of Vancomycin Binding Pocket in Designing Compounds Active Against Vancomycin-resistant Enterococci (VRE)

Jia, Yanxing; Bois‐Choussy, Michèle; Malabarba, Adriano; Brunati, Cristina

doi:10.1038/ja.2006.75

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…Another strategy leading to vancomycin derivatives that are active against VRE is the modification of the macrocyclic‐binding pocket (Jia et al , 2006a, b). The basic structural features of these biaryl ether‐containing macrocycles are: (1) deletion of the carboxyl group of vancomycin's central amino acid (amino acid D); (2) elongation of the N ‐terminal; and (3) presence of lipidated aminoglucose on the D‐ring.…”

Section: Vancomycin Groupmentioning

confidence: 99%

Sweet antibiotics – the role of glycosidic residues in antibiotic and antitumor activity and their randomization

2008

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A large number of antibiotics are glycosides. In numerous cases the glycosidic residues are crucial to their activity; sometimes, glycosylation only improves their pharmacokinetic parameters. Recent developments in molecular glycobiology have improved our understanding of aglycone vs. glycoside activities and made it possible to develop new, more active or more effective glycodrugs based on these findings - a very illustrative recent example is vancomycin. The majority of attention has been devoted to glycosidic antibiotics including their past, present, and probably future position in antimicrobial therapy. The role of the glycosidic residue in the biological activity of glycosidic antibiotics, and the attendant targeting and antibiotic selectivity mediated by glycone and aglycone in antibiotics some antitumor agents is discussed here in detail. Chemical and enzymatic modifications of aglycones in antibiotics, including their synthesis, are demonstrated on various examples, with particular emphasis on the role of specific and mutant glycosyltransferases and glycorandomization in the preparation of these compounds. The last section of this review describes and explains the interactions of the glycone moiety of the antibiotics with DNA and especially the design and structure-activity relationship of glycosidic antibiotics, including their classification based on their aglycone and glycosidic moiety. The new enzymatic methodology 'glycorandomization' enabled the preparation of glycoside libraries and opened up new ways to prepare optimized or entirely novel glycoside antibiotics.

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Section: Vancomycin Groupmentioning

confidence: 99%

Sweet antibiotics – the role of glycosidic residues in antibiotic and antitumor activity and their randomization

2008

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Vancomycin analogs: Seeking improved binding of d-Ala-d-Ala and d-Ala-d-Lac peptides by side-chain and backbone modifications

Leung

Tirado‐Rives

Jorgensen

2009

Bioorganic & Medicinal Chemistry

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In order to seek vancomycin analogs with improved performance against VanA and VanB resistant bacterial strains, extensive computational investigations have been performed to examine the effects of side-chain and backbone modifications. Changes in binding affinities for tripeptide cell wall precursor mimics, Ac 2 -L-Lys-D-Ala-D-Ala (3) and Ac 2 -L-Lys-D-Ala-D-Lac (4), with vancomycin analogs were computed with Monte Carlo/free energy perturbation (MC/FEP) calculations. Replacements of the 3-hydroxyl group in residue 7 with small alkyl or alkoxy groups, which improve contacts with the methyl side chain of the ligands' D-Ala residue, are predicted to be the most promising to enhance binding for both ligands. The previously reported amine backbone modification as in 5 is shown to complement the hydrophobic modifications for binding monoacetylated tripeptides. In addition, replacement of the hydroxyl groups in residues 5 and 7 by fluorine is computed to have negligible impact on binding the tripeptides, though it may be pharmacologically advantageous.

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Carbonyl catalysis enables a biomimetic asymmetric Mannich reaction

Chen

Gong

et al. 2018

Science

176

117

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Chiral amines are widely used as catalysts in asymmetric synthesis to activate carbonyl groups for α-functionalization. Carbonyl catalysis reverses that strategy by using a carbonyl group to activate a primary amine. Inspired by biological carbonyl catalysis, which is exemplified by reactions of pyridoxal-dependent enzymes, we developed an N-quaternized pyridoxal catalyst for the asymmetric Mannich reaction of glycinate with aryl -diphenylphosphinyl imines. The catalyst exhibits high activity and stereoselectivity, likely enabled by enzyme-like cooperative bifunctional activation of the substrates. Our work demonstrates the catalytic utility of the pyridoxal moiety in asymmetric catalysis.

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Importance of the Structure of Vancomycin Binding Pocket in Designing Compounds Active Against Vancomycin-resistant Enterococci (VRE)

Cited by 3 publications

References 25 publications

Sweet antibiotics – the role of glycosidic residues in antibiotic and antitumor activity and their randomization

Sweet antibiotics – the role of glycosidic residues in antibiotic and antitumor activity and their randomization

Vancomycin analogs: Seeking improved binding of d-Ala-d-Ala and d-Ala-d-Lac peptides by side-chain and backbone modifications

Carbonyl catalysis enables a biomimetic asymmetric Mannich reaction

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