Aromatic Esters of Bicyclic Amines as Antimicrobials against Streptococcus pneumoniae

Abstract

Díez-Martínez, R.; Maestro, B.; García-Fernández, E.; de Waal, B.F.M.; Meijer, E.W.; García, P.; Sanz, J.M.

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

“…This makes necessary the development of choline analogs that possesses a higher binding efficiency. In fact, CBMs display a broad ligand range [ 104 , 133 , 237 , 238 , 239 ] (see representative compounds in Figure 8 A) in which the minimal requirement for binding is that of a tertiary amine with two ethyl substituents or a quaternary amine with three methyl substituents [ 237 ]. The choline-binding sites are able to accommodate longer substituents provided they are non-polar.…”

“…Analysis of crystal complexes between CbpF and atropine points, as the major determinant for the stronger EBA binding compared to choline, to the simultaneous involvement of protein tryptophan residues in the binding site both with the ammonium group in the ligand (through cation-π forces) and with its aromatic moiety (involving T-shaped π-π stacking) [ 133 ] ( Figure 8 B). On the basis of these structural data, further screening of rationally designed chemical libraries of EBA derivatives for binding to the CBM from LytA (C-LytA protein) led to optimized compounds with a high content in aromatic rings ( Figure 8 A) that inhibit in vitro lytic activity of LytA with a 100-fold stronger efficiency than choline [ 239 ]. Moreover, these EBA derivatives arrest liquid pneumococcal cultures in vitro of both non-capsuled R6 and capsuled D39 strains, with minimal inhibitory concentrations (MIC) in the low micromolar range.…”

“…These values are comparable to usual β-lactam, macrolide, and fluoroquinolone antibiotics [ 245 ]. Bactericidal results were also validated in an in vivo zebrafish embryo model of infection, reaching 98% survival at a 2 μm concentration [ 239 ].…”

“…An alternative procedure is represented by a recent nanotechnological procedure that involves the use of a poly(propylene imine) dendrimer scaffold functionalized with several molecules of choline [ 246 ] or EBAs [ 239 ] ( Figure 9 ).…”

“…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 ]. Similar results were also obtained with the highly pathogenic AR33118 (serotype 3) strain, a pneumococcal clinical isolate that displays resistance to levofloxacin [ 239 ].…”