Flexible and Biocompatible Antifouling Polyurethane Surfaces Incorporating Tethered Antimicrobial Peptides through Click Reactions.

Efficient, simple antibacterial materials to combat implant-associated infections are much in demand. Herein, the development of polyurethanes, both cross-linked thermoset and flexible and versatile thermoplastic, suitable for "click on demand" attachment of antibacterial compounds enabled via incorporation of an alkyne-containing diol monomer in the polymer backbone, is described. By employing different polyolic polytetrahydrofurans, isocyanates, and chain extenders, a robust and flexible material comparable to commercial thermoplastic polyurethane is prepared. A series of short synthetic antimicrobial peptides are designed, synthesized, and covalently attached in a single coupling step to generate a homogenous coating. The lead material is shown to be biocompatible and does not display any toxicity against either mouse fibroblasts or reconstructed human epidermis according to ISO and OECD guidelines. The repelling performance of the peptide-coated materials is illustrated against colonization and biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis on coated plastic films and finally, on coated commercial central venous catheters employing LIVE/DEAD staining, confocal laser scanning microscopy, and bacterial counts. This study presents the successful development of a versatile and scalable polyurethane with the potential for use in the medical field to reduce the impact of bacterial biofilms.

Biofocussed chemoprospecting: An efficient approach for drug discovery.

Drug discovery strategies include from broad random screening to focussed target-based approaches. Structure and substrate information greatly enables target-based design, but this is limited to relatively few targets; cell-based screening can identify new targets but often suffers from low hit rates and difficult hit optimization. Thus, newer approaches are needed that can improve the efficiency of screening and hit optimization. Here, we describe an efficient approach for hit generation, which may be called "biofocussed chemoprospecting." With bio-likeness and ease of synthesis as priority criteria, libraries may be constructed with good optimization potential, physicochemical diversity, drug likeness and low cost. Following this approach, two libraries based on linear and cyclic dipeptide scaffolds were designed, first as virtual libraries comprising of more than 30000 compounds, and after subsequent filtering, as a small library of a total of 51 compounds. These provided good diversity at low cost, and were tested for bioactivities. The discovery of six active compounds demonstrates a hit rate greater than 10%. This is comparable to target-based approaches, but the "chemoprospecting" method described here has the additional potential to identify new targets and mechanisms.