Titre
Amoxicillin-resistant Streptococcus pneumoniae can be resensitized by targeting the mevalonate pathway as indicated by sCRilecs-seq.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Dewachter, L.
Auteure/Auteur
Dénéréaz, J.
Auteure/Auteur
Liu, X.
Auteure/Auteur
de Bakker, V.
Auteure/Auteur
Costa, C.
Auteure/Auteur
Baldry, M.
Auteure/Auteur
Sirard, J.C.
Auteure/Auteur
Veening, J.W.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2050-084X
Statut éditorial
Publié
Date de publication
2022-06-24
Volume
11
Première page
e75607
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
Antibiotic resistance in the important opportunistic human pathogen Streptococcus pneumoniae is on the rise. This is particularly problematic in the case of the β-lactam antibiotic amoxicillin, which is the first-line therapy. It is therefore crucial to uncover targets that would kill or resensitize amoxicillin-resistant pneumococci. To do so, we developed a genome-wide, single-cell based, gene silencing screen using CRISPR interference called sCRilecs-seq (subsets of CRISPR interference libraries extracted by fluorescence activated cell sorting coupled to next generation sequencing). Since amoxicillin affects growth and division, sCRilecs-seq was used to identify targets that are responsible for maintaining proper cell size. Our screen revealed that downregulation of the mevalonate pathway leads to extensive cell elongation. Further investigation into this phenotype indicates that it is caused by a reduced availability of cell wall precursors at the site of cell wall synthesis due to a limitation in the production of undecaprenyl phosphate (Und-P), the lipid carrier that is responsible for transporting these precursors across the cell membrane. The data suggest that, whereas peptidoglycan synthesis continues even with reduced Und-P levels, cell constriction is specifically halted. We successfully exploited this knowledge to create a combination treatment strategy where the FDA-approved drug clomiphene, an inhibitor of Und-P synthesis, is paired up with amoxicillin. Our results show that clomiphene potentiates the antimicrobial activity of amoxicillin and that combination therapy resensitizes amoxicillin-resistant S. pneumoniae. These findings could provide a starting point to develop a solution for the increasing amount of hard-to-treat amoxicillin-resistant pneumococcal infections.
Sujets
PID Serval
serval:BIB_93696BAFA5F6
PMID
Open Access
Oui
Date de création
2022-07-04T12:29:00.558Z
Date de création dans IRIS
2025-05-21T01:12:33Z
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Nom
35748540_BIB_93696BAFA5F6.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
4.89 MB
Format
Adobe PDF
PID Serval
serval:BIB_93696BAFA5F6.P001
URN
urn:nbn:ch:serval-BIB_93696BAFA5F60
Somme de contrôle
(MD5):77318c45f5db769434ab17364bcb1246