Angew Chem Int Ed Engl. 2015 Sep 17. doi: 10.1002/anie.201505700. [Epub ahead of print]

Aromatic Esters of Bicyclic Amines as Antimicrobials against Streptococcus pneumoniae.

de Gracia Retamosa M1,2, Díez-Martínez R3, Maestro B1, García-Fernández E3, de Waal B4, Meijer EW4, García P5, Sanz JM6.

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A double approach was followed in the search of novel inhibitors of the surface choline-binding proteins (CBPs) ofStreptococcus pneumoniae (pneumococcus) with antimicrobial properties. First, a library of 49 rationally-designed esters of alkyl amines was screened for their specific binding to CBPs. The best binders, being esters of bicyclic amines (EBAs), were then tested for their in vitro effect on pneumococcal growth and morphology. Second, the efficiency of EBA-induced CBP inhibition was enhanced about 45 000-fold by multivalency effects upon synthesizing a poly(propylene imine) dendrimer containing eight copies of an atropine derivative. Both approaches led to compounds that arrest bacterial growth, dramatically decrease cell viability, and exhibit a protection effect in animal disease models, demonstrating that the pneumococcal CBPs are adequate targets for the discovery of novel antimicrobials that overcome the currently increasing antimicrobial resistance issues.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


antibiotic resistance; choline-binding proteins; dendrimers; drug design; pneumococcus

PMID: 26377931 [PubMed - as supplied by publisher]