Synthesis and Biological Studies of Lanthionine Derivatives
type: CreativeWork
description: The widespread use of antibiotics has caused bacteria to become drug resistant. Efforts have been done by many research groups to identify new molecules as inhibitors or inactivators of resistant proteins like Penicillin Binding Proteins (PBPs) or to find new targets which allow putting peptidoglycan (PG) biosynthesis under control. The aim of this work is to develop a new labeling method for PG allowing to identify novel antibiotics and worthy target for inhibition. In Escherichia coli, meso-diaminopimelic acid (A2pm) is a key molecule for reticulation of PG. During this work, we synthesized meso-lanthionine, the monosulfur analogue of meso A2pm, and some of its derivatives. As these compounds are susceptible to enter PG biosynthesis via MurE enzymatic addition onto UDP (S) Ala γ (R) Glu, their use in a new labeling method has been investigated. Another approach was the introduction of labeled lanthionines in PG via the recycling pathway by replacement of the natural tripeptide (S) Ala γ (R)-Glu-meso-A2pm with tripeptide analogues containing modified lanthionines. We have developed a new stereoselective synthesis of the three lanthionine diastereomers (meso-Lan, (R,R)-Lan and (S,S)-Lan) and of an α-benzylated analogue. Good yields at the gram scale and excellent diastereomeric excesses (>99%), without any enrichment step, were obtained in aqueous solution. Biological experiments showed the incorporation of meso-Lan and (R,R)-Lan into PG. Upon this results, [35S]lanthionine diastereomers could be used to study the biosynthesis of PG and its turnover in relation to cell growth and division. Unfortunately, the α-benzylated lanthionine was not incorporated. This result indicates that the introduction of lanthionines with a substituted aromatic group at this position is not feasible via the reaction catalysed by MurE. We have also developed a synthesis of protected lanthionines bearing an α-alkyl group useful for the preparation of PG building block analogues. An enanti…
abstract: The widespread use of antibiotics has caused bacteria to become drug resistant. Efforts have been done by many research groups to identify new molecules as inhibitors or inactivators of resistant proteins like Penicillin Binding Proteins (PBPs) or to find new targets which allow putting peptidoglycan (PG) biosynthesis under control. The aim of this work is to develop a new labeling method for PG allowing to identify novel antibiotics and worthy target for inhibition. In Escherichia coli, meso-diaminopimelic acid (A2pm) is a key molecule for reticulation of PG. During this work, we synthesized meso-lanthionine, the monosulfur analogue of meso A2pm, and some of its derivatives. As these compounds are susceptible to enter PG biosynthesis via MurE enzymatic addition onto UDP (S) Ala γ (R) Glu, their use in a new labeling method has been investigated. Another approach was the introduction of labeled lanthionines in PG via the recycling pathway by replacement of the natural tripeptide (S) Ala γ (R)-Glu-meso-A2pm with tripeptide analogues containing modified lanthionines. We have developed a new stereoselective synthesis of the three lanthionine diastereomers (meso-Lan, (R,R)-Lan and (S,S)-Lan) and of an α-benzylated analogue. Good yields at the gram scale and excellent diastereomeric excesses (>99%), without any enrichment step, were obtained in aqueous solution. Biological experiments showed the incorporation of meso-Lan and (R,R)-Lan into PG. Upon this results, [35S]lanthionine diastereomers could be used to study the biosynthesis of PG and its turnover in relation to cell growth and division. Unfortunately, the α-benzylated lanthionine was not incorporated. This result indicates that the introduction of lanthionines with a substituted aromatic group at this position is not feasible via the reaction catalysed by MurE. We have also developed a synthesis of protected lanthionines bearing an α-alkyl group useful for the preparation of PG building block analogues. An enanti…
author: Denoël, Thibaut
language: en
keywords: chiral, enantioelective synthesis, sulfamidate, amino acid, peptide, serine, peptidoglycan, synthèse énantiosélective, acide aminé, sérine, peptidoglycane, Physical, chemical, mathematical & earth Sciences, Chemistry, Physique, chimie, mathématiques & sciences de la terre, Chimie
license: http://purl.org/coar/access_right/c_abf2
date published: 2014
date modified: 2026-07-24T02:49:27Z
provider: Université de Liège
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: ULiège - Université de Liège