Multivalent Choline Dendrimers Increase Phagocytosis of <b><i>Streptococcus pneumoniae </i></b>R6 by Microglial Cells

Abstract

Background: Pneumococcal virulence factors common to all serotypes, such as choline-binding proteins (CBPs), are promising therapeutic targets in pneumococcal infections. We studied the effect of a choline dendrimer with maximized binding affinity/specificity for CBPs on microglia-mediated pneumococcal phagocytosis. Methods: Pneumoccocal cultures were exposed to dendrimers containing 8 choline end groups or amino groups as controls, either from the beginning of bacterial growth or at the late exponential phase. The effect of long/short co-incubation was assessed in terms of bacterial morphological changes and increase in bacterial uptake by primary microglial cultures. Results: Inhibiting CBPs by micromolar concentrations of a choline dendrimer caused the formation of long pneumococcal chains that were readily phagocytosed by microglia. Enhanced phagocytosis was dendrimer dose-dependent. Long bacteria-dendrimer co-incubation (14 h) resulted in a higher bacterial uptake than short co-incubation (2 h; p < 0.001). Conclusions: Multivalent dendrimers containing choline end groups are promising antimicrobial agents for the management of pneumococcal diseases.

Bacterial meningitis: an update of new treatment options

“…An increase of bacterial phagocytosis can not only be achieved by stimulating the immune system of the host, but also by compounds which do not reduce bacterial growth but modify the bacterial surface thereby facilitating phagocytosis and intracellular killing [224].…”

Progress in the Application of Nanoparticles and Graphene as Drug Carriers and on the Diagnosis of Brain Infections

“…The extent of phagocytosis was dependent on the dendrimers dose. The terminal choline-containing multivalent dendrimers were found promising in pneumococcal diseases [61]. Similarly, quantum dots (QDs) are uniquely nanostructured with peculiar optical and physical properties and are used in biomedicine, biosensing, and optronics.…”

Choline Binding Proteins from Streptococcus pneumoniae: A Dual Role as Enzybiotics and Targets for the Design of New Antimicrobials

“…Since a dendrimer contains several ligand copies on its surface, and the CBPs contain, in turn, several binding sites, multimolecular complexes are likely to be produced ( Figure 9 B), so that the binding affinity increases exponentially rather than linearly for entropic reasons [ 247 ]. As a result, choline dendrimers harboring between 4 and 64 choline residues inhibit the CBP activity in vitro 10,000-fold more efficiently than free choline, causing inhibition of daughter cell separation after division [ 246 ] and favoring phagocytosis by microglial cells [ 248 ]. On the other hand, a dendrimer containing only 8 atropine molecules and termed g2-dendropine ( Figure 9 ) not only dramatically enhances its LytA inhibitory efficiency in vitro compared with atropine by 45,000-fold, with an IC 50 in the nanomolar range, but also turns the non-lytic activity shown by the choline dendrimers into a lytic response, so that a micromolar concentration is sufficient to completely abolish growth of the R6 strain [ 239 ].…”