Abstract
Streptococcus mutans is the most significant pathogenic bacterium implicated in the formation of dental caries and, both directly and indirectly, has been associated with severe conditions such as multiple sclerosis, cerebrovascular and peripheral artery disease. Polymers able to selectively bind S. mutans and/or inhibit its adhesion to oral tissue in a non-lethal manner would offer possibilities for addressing pathogenicity without selecting for populations resistant against bactericidal agents. In the present work two libraries of 2-(dimethylamino)ethyl methacrylate (pDMAEMA)-based polymers were synthesized with various proportions of either N,N,N-trimethylethanaminium cationic- or sulfobetaine zwitterionic groups. These copolymers where initially tested as potential macromolecular ligands for S. mutans NCTC 10449, whilst Escherichia coli MG1655 was used as Gram-negative control bacteria. pDMAEMA-derived materials with high proportions of zwitterionic repeating units were found to be selective for S. mutans, in both isolated and S. mutans–E. coli mixed bacterial cultures. Fully sulfobetainized pDMAEMA was subsequently found to bind/cluster preferentially Gram-positive S. mutans and S. aureus compared to Gram negative E. coli and V. harveyi. A key initial stage of S. mutans pathogenesis involves a lectin-mediated adhesion to the tooth surface, thus the range of potential macromolecular ligands was further expanded by investigating two glycopolymers bearing α-mannopyranoside and β-galactopyranoside pendant units. Results with these polymers indicated that preferential binding to either S. mutans or E. coli can be obtained by modulating the glycosylation pattern of the chosen multivalent ligands without incurring unacceptable cytotoxicity in a model gastrointestinal cell line. Overall, our results allowed to identify a structure–property relationship for the potential antimicrobial polymers investigated, and suggest that preferential binding to Gram-positive S. mutans could be achieved by fine-tuning of the recognition elements in the polymer ligands.
Highlights
The increasing development of resistance in bacteria to antibiotics is a universal threat to humans and animals,[1] and the detection and inactivation of bacteria remains a significant healthcare and societal challenge.[1,2,3] While much of the focus in addressing infections has been for acute systemic conditions, there are important healthcare considerations for chronic bacterial diseases, for example those occurring in the oral cavity
We recently showed that multivalent polymeric ligands can be engineered through a ‘bacteria-instructed synthesis’ where ligands are generated by using bacterial cell surfaces as templates, hijacking bacterial metal-binding and redox pathways to activate the required polymerization catalysts.[3]
The analyses of the mixed culture experiments demonstrate that there were negligible areas of fluorescence cross-over, which could be explained in terms of either non-specific binding of the polymer to E. coli or spatial proximity between red mCherry E. coli bacterial cells and green coumarin 343 (4)100%-S. mutans complexes. These results indicated that zwitterionic polymers were able to act as partially selective ligands for Gram-positive for S. mutans and S. aureus bacteria
Summary
The increasing development of resistance in bacteria to antibiotics is a universal threat to humans and animals,[1] and the detection and inactivation of bacteria remains a significant healthcare and societal challenge.[1,2,3] While much of the focus in addressing infections has been for acute systemic conditions, there are important healthcare considerations for chronic bacterial diseases, for example those occurring in the oral cavity. Lectin binding affinities can be significantly increased when multivalent sugar ligands are utilized,[31, 32] a phenomenon known as cluster glycoside effect.[33] multivalent carbohydrate ligands could potentially be utilized for binding /sequestration of S. mutans if suitable ligand architecture and sugar motifs were identified Bacteria differ in their surface chemical and structural features, and species-selective binding has been demonstrated using a number of methods, for example utilizing charge interactions,[3, 34] saccharide-based binding agents,[35,36,37,38] and cell structural mimics through templating[39,40,41] and antibiotics.[42] We recently showed that multivalent polymeric ligands can be engineered through a ‘bacteria-instructed synthesis’ where ligands are generated by using bacterial cell surfaces as templates, hijacking bacterial metal-binding and redox pathways to activate the required polymerization catalysts.[3] Polymer ligands are often used for bacterial binding studies due to their potential to span over receptors and chemical functionalities at the cell surface, and bind them in a multivalent fashion.[31, 32, 43, 44]. Bacterial cluster size was determined by laser diffraction using a Coulter LS230 particle size analyser (Beckman Coulter, High Wycombe, UK)
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