Aromatic esters of bicyclic amines as antimicrobials against streptococcus pneumoniae

M. De Gracia Retamosa, R. Díez-Martínez, B. Maestro, E. García-Fernández, B.F.M. De Waal, E. W. Meijer, P. García, J.M. Sanz

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Abstract

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.

Original languageEnglish
Pages (from-to)13673-13677
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number46
DOIs
Publication statusPublished - 1 Nov 2015

Keywords

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

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