Antifungal activity of a β-peptide in synthetic urine media: Toward materials-based approaches to reducing catheter-associated urinary tract fungal infections

Abstract

Catheter-associated urinary tract infections (CAUTI) are the most common type of hospital-acquired infection, with more than 30 million catheters placed annually in the US and a 10–30% incidence of infection. Candida albicans forms fungal biofilms on the surfaces of urinary catheters and is the leading cause of fungal urinary tract infections. As a step toward new strategies that could prevent or reduce the occurrence of C. albicans-based CAUTI, we investigated the ability of antifungal β-peptide-based mimetics of antimicrobial peptides (AMPs) to kill C. albicans and prevent biofilm formation in synthetic urine. Many α-peptide-based AMPs exhibit antifungal activities, but are unstable in high ionic strength media and are easily degraded by proteases—features that limit their use in urinary catheter applications. Here, we demonstrate that β-peptides designed to mimic the amphiphilic helical structures of AMPs retain 100% of their structural stability and exhibit antifungal and anti-biofilm activity against C. albicans in a synthetic medium that mimics the composition of urine. We demonstrate further that these agents can be loaded into and released from polymer-based multilayer coatings applied to polyurethane, polyethylene, and silicone tubing commonly used as urinary catheters. Our results reveal catheters coated with β-peptide-loaded multilayers to kill planktonic fungal cells for up to 21 days of intermittent challenges with C. albicans and prevent biofilm formation on catheter walls for at least 48 hours. These new materials and approaches could lead to advances that reduce the occurrence of fungal CAUTI.

Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application

“…Accordingly, there are many possible modifications ranging from the incorporation of unnatural amino acids (of which more than 700 are known [36]) and peptides with altered backbones, to entirely different chemical structures. These modifications and structural differences are often able to resolve stability and cytotoxicity issues [30,32,35]. Raman et al [30], for example, designed a β-peptide with anti-fungal and anti-biofilm activity against Candida albicans, which remained structurally stable and active in synthetic urine media.…”

“…These modifications and structural differences are often able to resolve stability and cytotoxicity issues [30,32,35]. Raman et al [30], for example, designed a β-peptide with anti-fungal and anti-biofilm activity against Candida albicans, which remained structurally stable and active in synthetic urine media. A peptidomimetic of 5 residues containing only arginine and biphenylalanine also showed anti-biofilm activity against multiple Gram-negative and Gram-positive bacteria, and exhibited very low toxicity to human erythrocytes and Vero monkey kidney epithelial cells, purportedly due to its short size and low hydrophobicity [32].…”

“…Recently used strategies to optimize anti-biofilm peptides include alteration of the amino acid composition, creation of hybrid peptides, and the design of structurally and functionally related compounds referred to as peptidomimetics [22,24,25,27,[29][30][31][32][33].…”

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

“…In view of the above-mentioned ability of antifungal β 3 -peptides to kill C. albicans and prevent its biofilm formation under CLSI conditions [ 242 , 244 ], it was of interest to elucidate whether these properties were retained in the presence of urine, being a prerequisite for their potential clinical use in preventing fungal CAUTI. In a model study, a fluorescent β 3 -peptide (i.e., coumarin-linker-[ACHC-β 3 hVal-β 3 hLys] 3 -NH 2 [ 242 ]) was shown to remain as a stable 14-helix (inferred by CD) and to exhibit antifungal and anti-biofilm activity against C. albicans in a synthetic medium mimicking the composition of urine [ 247 ]. The β 3 -peptide exhibited substantial antifungal activity in synthetic urine with a MIC of 16 µg/mL that was only 2-fold higher than its MIC under standard planktonic susceptibility testing conditions in RPMI medium.…”

The importance of fungal pathogens and antifungal coatings in medical device infections

“…Subsequently, polyethylene catheter tubes were explored using a different layer-by-layer coating method using either poly-L-lysine and poly-L-glutamic acid or chitosan (CH) and hyaluronic acid (HA); followed by beta-peptide loading (Raman et al, 2016a). The CH/HA layers had almost double the loading capacity of the PLL/PGA films and exhibited weak antifungal activity against C. albicans without the drug.…”