Click chemistry and T3SS Inhibition: Mechanistic Insights into Targeted Anti-Infective Strategies

Nhu Nguyen; Christopher Boddy

doi:10.18192/osurj.v5i2.8049

Chimie clic et inhibition du T3SS : perspectives mécanistiques sur les stratégies anti-infectieuses ciblées

Auteurs-es

Nhu Nguyen University of Ottawa, Ottawa, ON, Canada
Christopher Boddy University of Ottawa, Ottawa, ON, Canada

DOI :

https://doi.org/10.18192/osurj.v5i2.8049

Résumé

La résistance antibiotique est une cause principale de la mort mondialement et est prévue à s'aggraver dans les années à venir. De nouveaux médicaments avec des nouveaux mécanismes d'action sont nécessaires pour addresser ce problème. Le système de sécrétion de type III (SST3) est une nouvelle cible médicamenteuse prometteuse en raison de son rôle essentiel dans plusieurs infections bactériennes, notamment la chlamydia, les maladies diarrhéiques, la peste et les infections pulmonaires associées à la fibrose kystique. Le SST3 est un complexe protéique de l’ordre du mégadalton, en forme de seringue, qui sécrète des protéines pathogènes dans la cellule hôte, facilitant l’invasion et la colonisation de l’hôte. Des petites molécules capables de perturber le SST3 bloqueraient l’infection sans tuer le pathogène, ce qui en fait une nouvelle classe prometteuse de médicaments anti-virulence. Un récent criblage à haut débit basé sur des cellules a identifié l’un des premiers composés connus pour inhiber fortement l’activité du T3SS. Cette inhibition est indirecte, le traitement par C5 induisant une diminution de 3 à 57 fois de l’expression des gènes codant pour le SST3. Toutefois, le mécanisme de cette diminution d’expression reste inconnu. La chimie click est une stratégie de synthèse reposant sur une classe de réactions hautement efficaces, sélectives et fiables permettant d’assembler de plus petites briques moléculaires. Un exemple récompensé par le prix Nobel en chimie en 2022 est la cycloaddition azoture-alcyne catalysée par le cuivre. Les approches de type click ou bio-orthogonales s’alignent avec le système de sécrétion de type III (SST3) en permettant un marquage spécifique, minimal et non perturbateur des protéines à l’aide de petites fonctions chimiques, telles que l’azoture, l’alcyne, l’alcyne contraint et l’alcène. Après l’incorporation de ce groupe fonctionnel, une seconde étape appelée « ligation click » a lieu, alors, cette approche en deux étapes préserve donc mieux la fonction native que la fusion directe de marqueurs volumineux. Plutôt que de tuer les bactéries, des petites molécules peuvent être conçues pour inhiber la fonction du SST3, bloquant ainsi la capacité du pathogène à échapper au système immunitaire. En concevant des médicaments à spectre étroit, il est possible de désactiver les pathogènes tout en exerçant une pression de résistance plus faible.

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Publié-e

2026-06-17

Numéro

Vol. 5 No. 2 (2026)

Rubrique

Résumés d’initiation à la recherche en sciences au premier cycle

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