## 1 Introduction  
When [PERSON] in 1922 discovered the first natural antibiotic, the lysozyme, [1] able to \"lyse\" bacterial cells and in 1928, Penicillin, from the fungus _Penicillium notatum_, able to inhibit bacterial growth, [2] the dawn of the antibiotic age started. Later on, in 1939, [PERSON] isolated an antibacterial agent from _Basillus brevi_, called gramicidin [3]. Gramicidin demonstrated its broad-spectrum activity against Gram-positive and Gram-negative bacteria becoming the first antibiotic commercially manufactured and sold up to this day [4]. Since the discovery of human defensins, histatins and cathelicidins, antimicrobial peptides (AMPs) have been studied, sequenced, and synthesized in laboratory in order to be used in the clinic for the treatment of several bacterial, fungal and viral infections. Besides representing the first defense of the innate immune system against pathogens, [5] they also have immunomodulatory effects working as mediators of the infection-associated inflammation, recruiting, and enhancing the activity of leukocytes and the release of cytokines but also contributing to the infection control and resolution [6, 7].  
Besides humans, natural AMPs have been found in different kingdoms (animals, plants, bacteria, fungi but also archaea and protists) and registered in the AMP database([[https://aps.unmc.edu/](https://aps.unmc.edu/)]([https://aps.unmc.edu/](https://aps.unmc.edu/)), accessed on 3 rd November 2021) [8; 9]. Briefly, all AMPs share common features, such as a sequence composed of less than 100 amino acids (aa), [10] with the majority having between 10 and 60 aa [11]. Even if some anionic AMPs, rich in glutamic and aspartic acids, are negatively charged [12], almost all antimicrobial peptides have a net positive charge for the presence of a high number of lysine, arginine and histidine (protonated in acidic conditions) [13]. Finally, another common feature is represented by the hydrophobicity conferred by hydrophobic aa that often overcomes 50% of the total amino acid sequence [14]. The high lipophilicity is useful especially for the penetration in the biological membranes but considering the net charge, overall, AMPs are amphipathic molecules. The classifications are based on their structure or the presence/absence of recognizable motifs. AMPs could be \(\alpha\)-helix, \(\beta\)-sheet, linearly extended, both \(\alpha\)-helix and \(\beta\)-sheet, cyclic and with complex structure or, seen from a different perspective, tryptophan- and arginine-rich, histidine-rich, proline-rich and glycine-rich [15; 16].  
In the last decades, the increasing resistance to antibiotic treatments, i.e., Methicillin, Vanomycin-resistant _Staphylococcus aureus_ and the rise of species with intrinsic multi-drug resistance, such as _Candida auris_, highlights the need for the development of new agents [17; 18; 19]. It has been estimated that nowadays in the US every year 2.8 million people are infected by antibiotic-resistant microorganisms with a death rate of 35,000 people [20] and just in recent years the world was affected by a new pandemic virus (SARS-CoV-2) with 236 million cases and 5.9 million deaths up-to-date [21].  
Studies on the AMPs synthetic analogs provided a new tool to understand the different and unique modes of actions against diverse microorganisms. Thus, this review will focus on the improvements of their properties with respect to their natural counterpart, their activity on bacterial and fungal conserved structures, i.e., membranes and cell walls, as well as on biofilm formation, their antiviral properties and execution dynamics.  
The latest studies in vivo and in vitro will be discussed, with highlights on the successful therapeutic application despite drawbacks like toxicity and immunogenicity.