The interaction between Carbohydrates and the Antimicrobial Peptide P-113Tri is Involved in the Killing of Candida albicans

Abstract

The emergence of drug resistance to Candida albicans is problematic in the clinical setting. Therefore, developing new antifungal drugs is in high demand. Our previous work indicated that the antimicrobial peptide P-113Tri exhibited higher antifungal activity against planktonic cells, biofilm cells, and clinical isolates of Candida species compared to its parental peptide P-113. In this study, we further investigated the difference between these two peptides in their mechanisms against C. albicans. Microscopic examination showed that P-113 rapidly gained access to C. albicans cells. However, most of the P-113Tri remained on the cell surface. Moreover, using a range of cell wall-defective mutants and competition assays, the results indicated that phosphomannan and N-linked mannan in the cell wall are important for peptide binding to C. albicans cells. Furthermore, the addition of exogenous phosphosugars reduced the efficacy of the peptide, suggesting that negatively charged phosphosugars also contributed to the peptide binding to the cell wall polysaccharides. Finally, using a glycan array, P-113Tri, but not P-113, can bind to other glycans commonly present on other microbial and mammalian cells. Together, these results suggest that P-113 and P-113Tri have fundamental differences in their interaction with C. albicans and candidacidal activities.

Role of Protein Glycosylation in Interactions of Medically Relevant Fungi with the Host

“…These observations are likely to occur because the defensins and PAF26 interact with glycosylated protein targets that need post-translational modifications to bind the antifungal compounds. For the case of the antimicrobial peptide P-113Tri, derived from human histatin 5, it requires the presence of Och1 activity to display anti-C. albicans activity [7]. This is because most of the C. albicans cell wall phosphomannan is attached to the N-linked mannan outer chain, and Och1 catalyzes the first step in its elaboration [28,31].…”

“…This is because most of the C. albicans cell wall phosphomannan is attached to the N-linked mannan outer chain, and Och1 catalyzes the first step in its elaboration [28,31]. Loss of the N-linked outer chain implies loss of most of the phosphomannan, which confers the net negative charge of the cell surface, required for the binding and internalization of P-113Tri [7]. Disruption of C. albicans GPI7, a mannose-ethanolamine phosphotransferase that participates in GPI anchor synthesis, led to increments in the cell wall chitin, and as a consequence, cells showed increased resistance to caspofungin [143].…”

“…As mentioned, glycoproteins are involved in a wide range of biological processes which ensure cell stability [7]. For instance, they are a major constituent of the fungal cell wall and plasma membrane, and the biosynthetic pathways of these glycans have been thoroughly dissected in organisms such as Candida albicans and Saccharomyces cerevisiae.…”

Anti-Endotoxin 9-Meric Peptide with Therapeutic Potential for the Treatment of Endotoxemia

“…AMPs have been highlighted as alternatives to conventional antibiotics owing to their broad-spectrum bactericidal and immunomodulatory activities against MDR strains, and as promising agents for treating sepsis [15,23,32,33]. Some AMPs such as hLF1-11, P-113, and LL-37 effectively target pathogens through degradation of their outer cell membranes and they show particularly potent ability to neutralize endotoxins while simultaneously killing bacteria [34][35][36][37]. Despite these advantageous properties, poor cell selectivity and high cytotoxicity toward mammalian cells are major problems limiting the application of currently available AMPs in disease management.…”

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

“…Some AMPs are in the development stages of clinical trials. For example, hLF1-11 derived from human lactoferrin is in phase 1 trials [ 37 ], and P-113 derived from human histatin-5 [ 35 , 38 ] and Omiganan derived from indolicidin are in phase 3 trials [ 39 ]. Among these, hLF1-11 and P-113 show potency against gram-negative infections [ 40 , 41 ].…”