PUBLICATION
Aromatic Esters of Bicyclic Amines as Antimicrobials against Streptococcus pneumoniae
- Authors
- de Gracia Retamosa, M., Díez-Martínez, R., Maestro, B., García-Fernández, E., de Waal, B., Meijer, E.W., García, P., Sanz, J.M.
- ID
- ZDB-PUB-170214-114
- Date
- 2015
- Source
- Angewandte Chemie (International ed. in English) 54: 13673-7 (Journal)
- Registered Authors
- Keywords
- antibiotic resistance, choline-binding proteins, dendrimers, drug design, pneumococcus
- MeSH Terms
-
- Amines/chemical synthesis
- Amines/chemistry
- Amines/pharmacology*
- Animals
- Anti-Bacterial Agents/chemical synthesis
- Anti-Bacterial Agents/chemistry*
- Anti-Bacterial Agents/pharmacology*
- Bacterial Proteins/antagonists & inhibitors
- Bacterial Proteins/metabolism
- Cell Survival/drug effects
- Cell Wall/drug effects
- Dose-Response Relationship, Drug
- Esters/chemistry
- Esters/pharmacology*
- Microbial Sensitivity Tests
- Molecular Structure
- Pneumococcal Infections/drug therapy*
- Streptococcus pneumoniae/cytology
- Streptococcus pneumoniae/drug effects*
- Streptococcus pneumoniae/growth & development
- Structure-Activity Relationship
- Zebrafish/embryology
- Zebrafish/microbiology
- PubMed
- 26377931 Full text @ Angew. Chem. Int. Ed. Engl.
Citation
de Gracia Retamosa, M., Díez-Martínez, R., Maestro, B., García-Fernández, E., de Waal, B., Meijer, E.W., García, P., Sanz, J.M. (2015) Aromatic Esters of Bicyclic Amines as Antimicrobials against Streptococcus pneumoniae. Angewandte Chemie (International ed. in English). 54:13673-7.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping