title: Aromatic Esters of Bicyclic Amines as Antimicrobials against Streptococcus pneumoniae.
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.
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avda. de la Universidad s/n, 03202 Elche (Spain).|Present address: Universidad del País Vasco (UPV/EHU) and Donostia International Physics Center (DIPC) (Spain).
authors.forename: María
authors.initials: M
authors.lastname: de Gracia Retamosa
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas (CSIC) and CIBER de Enfermedades Respiratorias (CibeRes), Ramiro de Maeztu, 9, 28040 Madrid (Spain).
authors.forename: Roberto
authors.initials: R
authors.lastname: Díez-Martínez
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avda. de la Universidad s/n, 03202 Elche (Spain).
authors.forename: Beatriz
authors.initials: B
authors.lastname: Maestro
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas (CSIC) and CIBER de Enfermedades Respiratorias (CibeRes), Ramiro de Maeztu, 9, 28040 Madrid (Spain).
authors.forename: Esther
authors.initials: E
authors.lastname: García-Fernández
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600MB Eindhoven (The Netherlands).
authors.forename: Bas
authors.initials: B
authors.lastname: de Waal
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600MB Eindhoven (The Netherlands).
authors.forename: E W
authors.initials: EW
authors.lastname: Meijer
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas (CSIC) and CIBER de Enfermedades Respiratorias (CibeRes), Ramiro de Maeztu, 9, 28040 Madrid (Spain). pgarcia@cib.csic.es.
authors.forename: Pedro
authors.initials: P
authors.lastname: García
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avda. de la Universidad s/n, 03202 Elche (Spain). jmsanz@umh.es.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Sanz
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011008:Pneumococcal Infections / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D015027:Zebrafish / Q000196:embryology / Q000382:microbiology
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004952:Esters; C110344:SpsA protein, Streptococcus pneumoniae
keywords: antibiotic resistance; choline-binding proteins; dendrimers; drug design; pneumococcus