8-Thioalkyl-adenosine derivatives inhibit Listeria monocytogenes NAD kinase through a novel binding mode
Julie Paoletti
(1)
,
Liliane Assairi
(2, 3)
,
Muriel Gelin
(4, 5, 6)
,
Valerie Huteau
(1)
,
Marie -Anne Nahori
(7)
,
Olivier Dussurget
(8, 7)
,
Gilles Labesse
(4, 5, 6)
,
Sylvie Pochet
(1)
1
Chimie et Biocatalyse
2 U759 Unité Imagerie intégrative
3 INSERM - Institut National de la Santé et de la Recherche Médicale
4 CBS - Centre de Biochimie Structurale [Montpellier]
5 CNRS - Centre National de la Recherche Scientifique
6 UM - Université de Montpellier
7 UIBC - Interactions Bactéries-Cellules
8 USPC - Université Sorbonne Paris Cité
2 U759 Unité Imagerie intégrative
3 INSERM - Institut National de la Santé et de la Recherche Médicale
4 CBS - Centre de Biochimie Structurale [Montpellier]
5 CNRS - Centre National de la Recherche Scientifique
6 UM - Université de Montpellier
7 UIBC - Interactions Bactéries-Cellules
8 USPC - Université Sorbonne Paris Cité
Muriel Gelin
- Fonction : Auteur
- PersonId : 761011
- ORCID : 0000-0003-1320-8663
Olivier Dussurget
- Fonction : Auteur
- PersonId : 756866
- ORCID : 0000-0001-9924-0837
- IdRef : 180914103
Gilles Labesse
- Fonction : Auteur
- PersonId : 758379
- ORCID : 0000-0002-6861-3300
- IdRef : 069986045
Sylvie Pochet
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 852562
- ORCID : 0000-0002-7774-7861
Connectez-vous pour contacter l'auteur
Résumé
Increased resistance of pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials. Biosynthetic pathways of several cofactors important for bacterial growth, such as nicotinamide adenine dinucleotide phosphate (NADP), have been proposed as a promising source of antibiotic targets. Nicotinamide adenine dinucleotide kinases (NADK; EC 2.7.1.23) are attractive for inhibitor development, since they catalyze the phosphorylation of NAD to NADP, which is an essential step of NADP metabolism. We previously synthesized diadenosine derivatives that inhibited NADK from two human pathogens, Listeria monocytogenes and Staphylococcus aureus, in the micromolar range. They behave as NAD mimics with the 5',5'-diphosphate group substituted by a 8,5' thioglycolic bridge. In an attempt to improve inhibitory potency, we designed new NAD mimics based on a single adenosine moiety harboring a larger derivatization attached to the C8 position and a small group at the 5' position. Here we report the synthesis of a series of 8-thioalkyl-adenosine derivatives containing various aryl and heteroaryl moieties and their evaluation as inhibitors of L. monocytogenes NADK1, S. aureus NADK and their human counterpart. Novel, sub-micromolar inhibitors of LmNADK1 were identified. Surprisingly, most LmNADK1 inhibitors demonstrated a high selectivity index against the close staphylococcal ortholog and the human NADK. Structural characterization of enzyme-inhibitor complexes revealed the original binding mode of these novel NAD mimics.
Format du dépôt | Notice |
---|---|
Type de dépôt | Article dans une revue |
Résumé |
en
Increased resistance of pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials. Biosynthetic pathways of several cofactors important for bacterial growth, such as nicotinamide adenine dinucleotide phosphate (NADP), have been proposed as a promising source of antibiotic targets. Nicotinamide adenine dinucleotide kinases (NADK; EC 2.7.1.23) are attractive for inhibitor development, since they catalyze the phosphorylation of NAD to NADP, which is an essential step of NADP metabolism. We previously synthesized diadenosine derivatives that inhibited NADK from two human pathogens, Listeria monocytogenes and Staphylococcus aureus, in the micromolar range. They behave as NAD mimics with the 5',5'-diphosphate group substituted by a 8,5' thioglycolic bridge. In an attempt to improve inhibitory potency, we designed new NAD mimics based on a single adenosine moiety harboring a larger derivatization attached to the C8 position and a small group at the 5' position. Here we report the synthesis of a series of 8-thioalkyl-adenosine derivatives containing various aryl and heteroaryl moieties and their evaluation as inhibitors of L. monocytogenes NADK1, S. aureus NADK and their human counterpart. Novel, sub-micromolar inhibitors of LmNADK1 were identified. Surprisingly, most LmNADK1 inhibitors demonstrated a high selectivity index against the close staphylococcal ortholog and the human NADK. Structural characterization of enzyme-inhibitor complexes revealed the original binding mode of these novel NAD mimics.
|
Titre |
en
8-Thioalkyl-adenosine derivatives inhibit Listeria monocytogenes NAD kinase through a novel binding mode
|
Auteur(s) |
Julie Paoletti
1
, Liliane Assairi
2, 3
, Muriel Gelin
4, 5, 6
, Valerie Huteau
1
, Marie -Anne Nahori
7
, Olivier Dussurget
8, 7
, Gilles Labesse
4, 5, 6
, Sylvie Pochet
1
1
Chimie et Biocatalyse
( 216196 )
- Département de Biologie structurale et Chimie, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15
- France
2
U759 Unité Imagerie intégrative
( 516607 )
- France
3
INSERM -
Institut National de la Santé et de la Recherche Médicale
( 303623 )
- 101, rue de Tolbiac, 75013 Paris
- France
4
CBS -
Centre de Biochimie Structurale [Montpellier]
( 59411 )
- 29 rue de Navacelles 34090 Montpellier Cedex
- France
5
CNRS -
Centre National de la Recherche Scientifique
( 441569 )
- France
6
UM -
Université de Montpellier
( 410122 )
- 163 rue Auguste Broussonnet - 34090 Montpellier
- France
7
UIBC -
Interactions Bactéries-Cellules
( 2962 )
- Département Biologie cellulaire et infection, 25-28 rue du Docteur Roux, F-75724 Paris Cedex 15
- France
8
USPC -
Université Sorbonne Paris Cité
( 303171 )
- Université Sorbonne Paris Cité | 100-104, avenue de France | 75013 Paris
- France
|
Public visé |
Scientifique
|
Sous-type de document pour les Articles |
Research article
|
Licence |
Paternité - Partage selon les Conditions Initiales
|
Version du document |
version éditeur
|
Comité de lecture |
Oui
|
Audience |
Non spécifiée
|
Date de publication |
2016
|
Volume |
124
|
Page/Identifiant |
1041-1056
|
Vulgarisation |
Non
|
Langue du document |
Anglais
|
Nom de la revue |
|
Domaine(s) |
|
Financement |
|
Projet(s) ANR |
|
Voir aussi |
|
Mots-clés (Mesh) |
|
Mots-clés |
en
Adenosine analogue, Antibacterial, Inhibitor, NAD kinase, X-ray crystallography
|
DOI | 10.1016/j.ejmech.2016.10.033 |
ProdINRA | 387353 |
Pubmed Id | 27783975 |
UT key WOS | 000388544600082 |
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