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

Abstract

Streptococcus pneumoniae (pneumococcus) is an important pathogen responsible for acute invasive and non-invasive infections such as meningitis, sepsis and otitis media, being the major cause of community-acquired pneumonia. The fight against pneumococcus is currently hampered both by insufficient vaccine coverage and by rising antimicrobial resistances to traditional antibiotics, making necessary the research on novel targets. Choline binding proteins (CBPs) are a family of polypeptides found in pneumococcus and related species, as well as in some of their associated bacteriophages. They are characterized by a structural organization in two modules: a functional module (FM), and a choline-binding module (CBM) that anchors the protein to the choline residues present in the cell wall through non-covalent interactions. Pneumococcal CBPs include cell wall hydrolases, adhesins and other virulence factors, all playing relevant physiological roles for bacterial viability and virulence. Moreover, many pneumococcal phages also make use of hydrolytic CBPs to fulfill their infectivity cycle. Consequently, CBPs may play a dual role for the development of novel antipneumococcal drugs, both as targets for inhibitors of their binding to the cell wall and as active cell lytic agents (enzybiotics). In this article, we review the current state of knowledge about host- and phage-encoded pneumococcal CBPs, with a special focus on structural issues, together with their perspectives for effective anti-infectious treatments.

Coinfinder: Detecting Significant Associations and Dissociations in Pangenomes

“…Another 3 genes co-occurring with the V-ATPase complex belong to the dpnMAB operon which encode the DpnII system implicated in DNA transformation (among other functions) (25) and an additional 3 are homologous to transposase IS66-related domains, perhaps suggesting how this operon has been horizontally transferred in this species (Figure 2b-c). Additionally, 4 of these proteins contained a putative cell wall binding repeat ("CW_binding_1") which has been implicated in choline binding (26). Choline-binding proteins (CBPs) contain a choline-binding module/domain which allows them to bind to the cell wall of S. pneumoniae, functioning as essential elements of cell division, as well as strong determinants of virulence (26) (27).…”

Roles of Amphipathicity and Hydrophobicity in the Micelle‐Driven Structural Switch of a 14‐mer Peptide Core from a Choline‐Binding Repeat

“…On the whole, these results reinforce the idea that details of the cross-strand interactions,p articularly with the participation of Trpr esidues, [14b, 23d, 25] are essential to b-hairpin formation in CBRs, as ac onsequence of the sub-optimal b-turn sequences. In fact, residues Trp3, Lys5, Trp10 and Tyr12 are extremelyc onservedi nt hesep ositions (> 30 %) in the approximately 90 CBRs already described for S. pneumoniae, [3] pointingt oa ne s-sentiald ual role for these amino acids both as native hairpin stabilisers and as participants in choline binding. [3] Determinantso fa-helix formation in micelles All designed variantse ither maintain or decrease to av ariable extent both the hydrophobicity of the peptides and the amphipathicity of the putative a-helix to be inserted in DPC micelles (Table 1);h ence, an increase of helix propensity was not necessarily expected.…”

“…In fact, residues Trp3, Lys5, Trp10 and Tyr12 are extremelyc onservedi nt hesep ositions (> 30 %) in the approximately 90 CBRs already described for S. pneumoniae, [3] pointingt oa ne s-sentiald ual role for these amino acids both as native hairpin stabilisers and as participants in choline binding. [3] Determinantso fa-helix formation in micelles All designed variantse ither maintain or decrease to av ariable extent both the hydrophobicity of the peptides and the amphipathicity of the putative a-helix to be inserted in DPC micelles (Table 1);h ence, an increase of helix propensity was not necessarily expected. Nevertheless, all variants except S3S10-LytA 239-252 still acquireasignificant extent of a-helicalc onformation in the presence of DPC micelles (Table 2), comparable to the wild-type form, demonstrating that incorporation of some polar side chains in the hydrophobic face of the helix (leadingt oad ecreased hydrophobic moment) does not prevent insertion into am icelle.…”

“…Choline-binding repeats( CBRs) are widespread motifs of approximately 20 amino acids that usuallyc onsist of a b-hairpin of 14 amino acids followed by al inker of 6-7 residues. [3] They are employed in an umber of surfacep roteins for the recognition of choline in the cell wall of various microorganisms such as Streptococcusp neumoniae (pneumococcus), and play an essentialr ole in bacterial viabilitya nd virulence. The CBRs belong, in turn, to the extensive CW binding 1m otif family that can be found in many different species( PFAM code PF01473, http://pfam.xfam.org/family/PF01473).…”

Morin Moderates the Biotoxicity of Pneumococcal Pneumolysin by Weakening the Oligomers’ Formation

“…Our subsequent animal experiments confirmed its effectiveness to remedy pulmonary injuries caused by S. pneumoniae-induced pneumonia in a murine model; meanwhile, morin also has anti-inflammatory activity and an ability to inhibit viable bacteria in organs to promote recovery. 31) For future prospects of S. pneumoniae anti-virulence medicaments, perhaps pneumolysin and choline binding proteins (CBPs) should be prioritized, 1,32) as these two targets are inextricably linked to the pathogenesis of S. pneumoniae. Although pneumolysin participates in a wide panoply of physiological processes, the study of molecular drugs and vaccines that explicitly target pneumolysin remain in their infancy.…”