Premium
Aromatic Esters of Bicyclic Amines as Antimicrobials against Streptococcus pneumoniae
Author(s) -
de Gracia Retamosa María,
DíezMartínez Roberto,
Maestro Beatriz,
GarcíaFernández Esther,
de Waal Bas,
Meijer E. W.,
García Pedro,
Sanz Jesús M.
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201505700
Subject(s) - antimicrobial , streptococcus pneumoniae , bicyclic molecule , chemistry , combinatorial chemistry , pneumococcal infections , in vitro , imine , dendrimer , bacterial growth , stereochemistry , biochemistry , bacteria , organic chemistry , biology , antibiotics , catalysis , genetics
A double approach was followed in the search of novel inhibitors of the surface choline‐binding proteins (CBPs) of Streptococcus 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.