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Article dans une revue Journal of Medicinal Chemistry Année : 2019

Anti-biofilm Agents against Pseudomonas aeruginosa : A Structure–Activity Relationship Study of C -Glycosidic LecB Inhibitors

Résumé

Biofilm formation is a key mechanism of antimicrobial resistance. We have recently reported two classes of orally bioavailable C-glycosidic inhibitors of the Pseudomonas aeruginosa lectin LecB with anti-biofilm activity. They proved efficient in target binding, were metabolically stable, non-toxic, selective and potent in inhibiting formation of bacterial biofilm. Here, we designed and synthesized 6 new carboxamides and 24 new sulfonamides for a detailed structure-activity-relationship for two clinically representative LecB variants. Sulfonamides generally showed higher inhibition compared to carboxamides which was rationalized based on crystal structure analyses. Substitutions at the thiophenesulfonamide increased binding through extensive contacts with a lipophilic protein patch. These metabolically stable compounds showed a further increase in potency towards the target and in biofilm inhibition assays. In general, we established the structure-activity relationship for these promising anti-biofilm agents and showed that modification of the sulfonamide residue bears future optimization potential. 1
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Dates et versions

hal-02349120, version 1 (06-11-2020)

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Roman Sommer, Katharina Rox, Stefanie Wagner, Dirk Hauck, Sarah Henrikus, et al.. Anti-biofilm Agents against Pseudomonas aeruginosa : A Structure–Activity Relationship Study of C -Glycosidic LecB Inhibitors. Journal of Medicinal Chemistry, 2019, 62 (20), pp.9201-9216. ⟨10.1021/acs.jmedchem.9b01120⟩. ⟨hal-02349120⟩
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