Abstract
Due to the increasing prevalence of drug-resistant fungi and the limitations of current treatment strategies to fungal infections, exploration and development of new antifungal drugs or substituents are necessary. In the study, a novel antimicrobial peptide, named Sparamosin, was identified in the mud crab Scylla paramamosain, which contains a signal peptide of 22 amino acids and a mature peptide of 54 amino acids. The antimicrobial activity of its synthetic mature peptide and two truncated peptides (Sparamosin1–25 and Sparamosin26–54) were determined. The results showed that Sparamosin26–54 had the strongest activity against a variety of Gram-negative bacteria, Gram-positive bacteria and fungi, in particular had rapid fungicidal kinetics (killed 99% Cryptococcus neoformans within 10 min) and had potent anti-biofilm activity against C. neoformans, but had no cytotoxic effect on mammalian cells. The RNA-seq results showed that after Sparamosin26–54 treatment, the expression of genes involved in cell wall component biosynthesis, cell wall integrity signaling pathway, anti-oxidative stress, apoptosis and DNA repair were significantly up-regulated, indicating that Sparamosin26–54 might disrupt the cell wall of C. neoformans, causing oxidative stress, DNA damage and cell apoptosis. The underlying mechanism was further confirmed. Sparamosin26–54 could bind to several phospholipids in the cell membrane and effectively killed C. neoformans through disrupting the integrity of the cell wall and cell membrane observed by electron microscope and staining assay. In addition, it was found that the accumulation of reactive oxygen species (ROS) increased, the mitochondrial membrane potential (MMP) was disrupted, and DNA fragmentation was induced after Sparamosin26–54 treatment, which are all hallmarks of apoptosis. Taken together, Sparamosin26–54 has a good application prospect as an effective antimicrobial agent, especially for C. neoformans infections.
Highlights
In addition to the serious threats caused by various virus outbreaks and drug-resistant bacterial infections, fungal infections are similar headlines today
Sparamosin1−25 and Sparamosin26−54, were designed and synthesized based on the secondary structure of Sparamosin mature peptide, which has two predicted α-helices located at residues Ile13Phe24 and residues Pro31-Arg39, respectively (Figures 1B,C)
The results showed that unlike the other two synthetic peptides (Sparamosin and Sparamosin1−25), the physicochemical parameters of Sparamosin26−54 have values closer to those defined for Antimicrobial peptides (AMPs)
Summary
In addition to the serious threats caused by various virus outbreaks and drug-resistant bacterial infections, fungal infections are similar headlines today. It is estimated that more than 1 billion people worldwide suffer from fungal diseases (Felix et al, 2017). Invasive fungal infections mainly occur in immunocompromised patients, such as those infected with HIV or undergoing chemotherapy, which is associated with unacceptably high mortality (Miceli et al, 2011). It is estimated that nearly 2 million people die from fungal infections each year, and the death toll continues to rise (Pappas et al, 2010; Brown et al, 2012). An estimated 223,100 cases of cryptococcal meningitis occur each year, resulting in 181,100 deaths (Rajasingham et al, 2017). Most deaths are reported to occur in low- and middle-income countries due to the lack of essential medicines and the high cost of effective treatment (Loyse et al, 2019)
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