| The work presented in this thesis focuses on developing antifungal 14-helical beta-peptidomimetics of antimicrobial peptides and devising materials-based strategies to deliver beta-peptides to kill Candida albicans cells and prevent biofilm formation on medical devices such as catheter tubes. This work describes (i) characterization of the antifungal activities of different 14-helical beta-peptides to identify potent antifungal beta-peptides, and (ii) development of materials-based strategies that can be applied to catheters, that gradually release beta-peptides to kill C. albicans cells and prevent biofilm formation in vitro and in vivo using a rat venous catheter model. The first section demonstrates that the hydrophobicity and helicity of 14-helical beta-peptides cooperatively control antifungal activity. Hydrophobic beta-peptides exhibit antifungal activity and prevent biofilm formation of multiple clinically relevant planktonic Candida strains and species. The ability of beta-peptides to prevent fungal biofilm formation motivates studies in the second section directed toward the development of polyelectrolyte multilayer-based materials platforms that gradually release beta-peptides as prophylactic strategies to prevent biofilm formation inside catheter tubes. A 'fill-and-purge' method was utilized to fabricate multilayers consisting of (i) poly-L-lysine and poly-L-glutamic acid, or (ii) hyaluronic acid and chitosan, which were then infused with antifungal beta-peptides. Our results indicate that beta-peptide structure, polyelectrolyte structure, and film composition influence the loading and release behaviors of beta-peptides, as well as the antifungal activities of coated catheter tubes. A comparison of the coated catheters under different conditions (e.g., in standard media, in vitro, in vivo, in synthetic urine media, as mixed biofilms, etc.) revealed differences in the extent of antifungal and anti-biofilm activities of the two multilayer systems inherently (without beta-peptide) and on beta-peptide loading. Finally, we describe an approach to improving the inherent anti-fouling properties of polymeric slippery liquid-infused porous surfaces (SLIPS) that involves releasing a broad-spectrum antimicrobial agent from polymeric and oil phases to kill planktonic fungi and bacteria. The versatility of the layer-by-layer methods used in these studies suggests additional opportunities to exploit these novel antimicrobial agents and materials-based approaches to design multi-functional coatings that prevent or reduce device-associated microbial infections in other biomedical contexts. |
