# Antimicrobial Peptides--Mechanisms of Action, Antimicrobial Effects and Clinical Applications
## 3 Antimicrobial Effects of AMPs
### Antifungal Activity of AMPs  
The excessive and improper use of systemic antibiotics, immunosuppressive therapy, chemotherapy, and radiotherapy have increased fungal infections in the general population [70; 71; 72]. The limited choice of antifungal therapy, which includes only four chemical types of systemic antifungals--polyenes, azoles, echinocandins, and flucytoises [71; 73]--as well as the increase in the resistance of specific strains to the mentioned antifungal drugs,  
Figure 5: Antibacterial activity mechanisms of AMPs. leads to increased morbidity and mortality, but also a dire need for alternative solutions in antifungal treatment [70; 71; 74]. Antifungal peptides (AFPs) could be a promising therapy for fungal infections [71; 75]. Most AFPs achieve their activity through membrane-associated mechanisms and specific targets. Differences in fungal membranes are sphingolipid composition, PI content, and ergosterol as the main membrane sterol. Specific targets such as glucosylcramides, mannosyldinositol phosphoryleximide, or a fungal protein target enable high selectivity and avoid resistance to therapy [76]. AFPs can be classified in accordance with a number of criteria, such as structure, mode of action, or origin [77]. However, the most accepted classification is according to the origin, which divides peptides into natural, semisynthetic, and synthetic ones [78]. Natural AFPs are produced by different species like Archaea, Bacteria, and Eukaryotes [77]. Natural AFPs have an \(\alpha\)-helix structure, \(\beta\)-hairpin or sheet, or combination of \(\alpha\)-helix and \(\beta\)-sheet, and depending on the amino acid in the most significant composition. They are classified as glycine-rich, arginine-rich, proline-rich, histidine-rich, and tryptophan-rich peptides [79]. Semisynthetic and synthetic peptides are designed to improve pharmacological properties and reduce immunogenicity and side effects caused by natural peptides [77]. Biophysical characteristics such as net charge, stereospecificity, hydrophobicity, secondary structure, peptide length, and amphipactivity determine the antifungal activity of peptides [80]. For example, an increase in the positive net charge can cause a stronger action on the membrane. Likewise, increased hydrophobicity and amphipactivity lead to increased antifungal activity [77]. The most abundant peptides harmful to the fungal biofilm are peptides of mammalian origin, defensins, cathelicidins, and histatins [71]. Defensins are isolated from not only mammals but also plants [81]. They are structurally organized as \(\alpha\)-helix and triple-stranded antiparallel \(\beta\)-sheet, which are connected by disulfide bonds that ensure the stability of the structure, even in extreme conditions [82]. Defensins from vertebrate animals are cationic and amphipatible peptides and can be divided into two subfamilies, \(\alpha\)-defensins and \(\beta\)-defensins [83]. Human \(\alpha\)-defensin 6 (HD6) prevents the adhesion of _Candida albicans_ (_C. albicans_) to human intestinal epithelial cells and, thus, biofilm formation [84]. \(\beta\)-defensin-1 displays inhibitory activity against germinating conidiaia of _Aspergillus fumigatus_[85]. Synthetic defensin-like peptides like \(\alpha\)-defensin-3, \(\beta\)-defensin-1, \(\beta\)-defensin-3, and PG-1 express antifungal activity against _Cryptococcus neoformans_ biofilms, including both planktonic cells and mature biofilm [86]. Cathelicidins are cationic peptides isolated from different species of mammals, consisting of 12-80 amino acids [71; 87]. The human antimicrobial peptide LL-37 was proven to inhibit _C. albicans_ cell adhesion on polystyrene and silicon surfaces, and BMAP-28, a bovine antimicrobial peptide, was able to reduce the number of C. _albicans_ adherent cells on silicone surfaces and inhibit its mature biofilm [88; 89; 90]. Histatins are human salivary peptides, first isolated from human parotid saliva, with polar and hydrophilic properties and \(\alpha\)-helix structural conformation in organic solutions [91].