Candida albicans is the most common fungal pathogen isolated from humans and is a leading cause of hospital-acquired infections. Systemic candidemia, an often fatal disease, is typically associated with C. albicans biofilms formed on the surface of indwelling medical devices. The goal of our project is to develop a novel strategy to prevent C. albicans biofilm formation on catheters, and to thereby reduce the incidence of candidemia in high-risk patients. In prior work the PI identified that cationic, amphiphilic oligomers of ?-amino acids (called ?-peptides) can exhibit high levels of specific activity against C. albicans as compared to mammalian cells. These ?-peptides were designed based on structural similarity to natural antimicrobial peptides, which typically fold into amphiphilic cationic helices when associated with cellular membranes. However, ?-peptides can be designed to possess key advantages over a-peptide antimicrobial peptides including activity at physiologic pH and ionic strength, greater structural stability, and resistance to proteolytic degradation. Here, we will design active and selective helical -peptides compounds and assess their ability to prevent C. albicans biofilm formation in vitro and in vivo. Additionally, we will investigate the specific antifungal activity of mixed a/?-peptides, which also fold into amphiphilic helices, and permit regulation of structure beyond that of ?-peptides. To facilitate delivery of antifungal ?- and a/?-peptides from the surface of medical devices we will design polyelectrolyte multilayer (PEM) films that incorporate and release the peptides at rates relevant for prevention of biofilm formation in vivo in catheter applications. We will assess how film thickness, film crosslinking, and peptide structures and chemical properties influence rate of release. The ability of antifungal ?- and a/?-peptides to inhibit C. albicans biofilm formation will be quantified in vitro by determining biofilm formation rate and biofilm structure on substrates coated with peptide-incorporated PEM films. Optimized peptides and release strategies will then be assessed in vivo using a rat central venous catheter model. Together these results will test the prediction that delivery of ?- and a/?-peptide oligomers from a PEM film on a catheter will inhibit C. albicans biofilm formation, and may establish a new paradigm for prevention of device-associated candidemia.
Design of ?- and a/?-peptides that specifically target Candida albicans cells and development of a polyelectrolyte multilayer (PEM) film based method to deliver these molecules from a catheter surface will prevent C. albicans biofilm formation and reduce incidence of candidemia in high-risk patients. Moreover, structure-function analysis of ?- and a/?-peptide activity and specificity will provide fundamental insight into structural features that permit selectivity for fungal cells and facilitate efforts to design novel antifungal agents. Likewise, experiments that investigate incorporation and release of ?- and a/?-peptides from PEM films will improve our ability to deliver a variety of compounds from film-coated substrates.
|Raman, Namrata; Lee, Myung-Ryul; Palecek, Sean P et al. (2014) Polymer multilayers loaded with antifungal ?-peptides kill planktonic Candida albicans and reduce formation of fungal biofilms on the surfaces of flexible catheter tubes. J Control Release 191:54-62|
|Lee, Myung-Ryul; Raman, Namrata; Gellman, Samuel H et al. (2014) Hydrophobicity and helicity regulate the antifungal activity of 14-helical ?-peptides. ACS Chem Biol 9:1613-21|
|Liu, Runhui; Chen, Xinyu; Falk, Shaun P et al. (2014) Structure-activity relationships among antifungal nylon-3 polymers: identification of materials active against drug-resistant strains of Candida albicans. J Am Chem Soc 136:4333-42|