REVIEW published: 14 June 2021 doi: 10.3389/fcimb.2021.668632 Antimicrobial Peptides: A New Hope in Biomedical and Pharmaceutical Fields † † † † Antonio Moretta 1 , Carmen Scieuzo 1,2 , Anna Maria Petrone 1 , Rosanna Salvia 1,2 , Michele Dario Manniello 1, Antonio Franco 1,2, Donatella Lucchetti 3, Antonio Vassallo 1, Heiko Vogel 4, Alessandro Sgambato 3,5* and Patrizia Falabella 1,2* 1 Department of Sciences, University of Basilicata, Potenza, Italy, 2 Spinoff XFlies s.r.l, University of Basilicata, Potenza, Italy, 3 Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy, 4 Department of Edited by: Entomology, Max Planck Institute for Chemical Ecology, Jena, Germany, 5 Centro di Riferimento Oncologico della Basilicata Francesc Rabanal, (IRCCS-CROB), Rionero in Vulture, Italy University of Barcelona, Spain Reviewed by: Surajit Bhattacharjya, Antibiotics are essential drugs used to treat pathogenic bacteria, but their prolonged use Nanyang Technological University, contributes to the development and spread of drug-resistant microorganisms. Antibiotic Singapore resistance is a serious challenge and has led to the need for new alternative molecules less Clara Balleste, Instituto Salud Global Barcelona prone to bacterial resistance. Antimicrobial peptides (AMPs) have aroused great interest (ISGlobal), Spain as potential next-generation antibiotics, since they are bioactive small proteins, naturally *Correspondence: produced by all living organisms, and representing the first line of defense against fungi, Patrizia Falabella fi [email protected] viruses and bacteria. AMPs are commonly classi ed according to their sources, which are Alessandro Sgambato represented by microorganisms, plants and animals, as well as to their secondary [email protected] structure, their biosynthesis and their mechanism of action. They find application in † These authors have contributed different fields such as agriculture, food industry and medicine, on which we focused our equally to this work and share first authorship attention in this review. Particularly, we examined AMP potential applicability in wound healing, skin infections and metabolic syndrome, considering their ability to act as Specialty section: potential Angiotensin-Converting Enzyme I and pancreatic lipase inhibitory peptides as This article was submitted to Clinical Microbiology, well as antioxidant peptides. Moreover, we argued about the pharmacokinetic and a section of the journal pharmacodynamic approaches to develop new antibiotics, the drug development Frontiers in Cellular and Infection Microbiology strategies and the formulation approaches which need to be taken into account in Received: 16 February 2021 developing clinically suitable AMP applications. Accepted: 10 May 2021 Keywords: drug-resistant microorganisms, antimicrobial peptides, biomedical and pharmacological applications, Published: 14 June 2021 pharmacokinetics and pharmacodynamics, drug delivery Citation: Moretta A, Scieuzo C, Petrone AM, Abbreviations: ACE, Angiotensin-Converting Enzyme I; AMP, Antimicrobial Peptide; APD, Antimicrobial Peptide Database; Salvia R, Manniello MD, Franco A, API, Active pharmaceutical ingredient; DDS, Drug Delivery System; Di-Phe, di-phenylalanine; EGFR, Epidermal Growth Lucchetti D, Vassallo A, Vogel H, Factor Receptor; EPL, ϵ-poly-L-lysine; GMO, Glyceryl Monooleate; HBBD, HG-Based Burn Dressings; hBD, Human b Sgambato A and Falabella P (2021) defensin; HG, Hydrogel; IPTG, Isopropyl b- D-1-Thiogalactopyranoside; LPS, Lipopolysaccharides; MRSA, Methicillin- Antimicrobial Peptides: A New Hope in resistant Staphylococcus aureus; PD, Pharmacodynamics; PK, Pharmacokinetics; SARS-CoV-2, Severe Acute Respiratory Biomedical and Pharmaceutical Fields. Syndrome Coronavirus 2; SCID, Severe Combined Immunodeficiency; TLR, Toll-like receptor; WHO, World Health Front. Cell. Infect. Microbiol. 11:668632. Organization; BPS, block polymeric structure; CB, cubosome; CMC, Critical Micelle Concentration; PA, peptide doi: 10.3389/fcimb.2021.668632 amphiphiles; SPPS, Solid Phase Peptide Synthesis. Frontiers in Cellular and Infection Microbiology | www.frontiersin.org1 June 2021 | Volume 11 | Article 668632 Moretta et al. AMPs: Biomedical and Pharmacological Applications INTRODUCTION AMP Properties and Biosynthesis Natural AMPs are evolutionary conserved gene-encoded A wide variety of antimicrobial agents are available today and molecules with structural and functional diversity, which is they are broadly applied to treat different types of human responsible for their wide range of activities against different infections. Specifically, antibiotics are powerful drugs used for pathogens in various organisms (Zhang and Gallo, 2016). treatments of pathogenic bacteria (Lei et al., 2019). However, However, although displaying considerable diversity in their their indiscriminate and prolonged use, especially in developing physio-chemical and structural properties, origins and countries, in both human and veterinary medicine, as well as in mechanisms of action, AMPs share some common features agriculture have contributed to the development and spread of (Moravej et al., 2018). Indeed, they are mostly short molecules drug-resistant microorganisms (Huan et al., 2020). As the World (<100 amino acids) (Pasupuleti et al., 2012), typically with a Health Organization (WHO) has extensively announced, the positive net charge (generally ranging from +2 to +11) and a alarming rise globally in resistance towards conventional notable proportion of hydrophobic residues (typically 50%) antimicrobials represents a potential and serious risk to public (Haney et al., 2017). They display an amphipathic structure, as health (Luong et al., 2020). Therefore, the antibiotic resistance they contain both hydrophobic and hydrophilic regions, that issue has made it urgent to search for alternatives to conventional enable them to be soluble in aqueous environments (Boparai and antibiotics, with novel modes of action and less predisposed to Sharma, 2020). A less common class of AMPs is represented by bacterial resistance. In the quest of new antibiotics, the the anionic AMPs, which have a negative net charge ranging antimicrobial peptides (AMPs), also known as host defense from -1 to -7 and have been identified in vertebrates, peptides, have recently raised great interest (Haney et al., 2019; invertebrates and plants (Harris et al., 2009). They include Bhattacharjya and Straus, 2020; Mahlapuu et al., 2020). Current many negatively charged aspartic and glutamic acid residues, research is focused on these natural compounds as innovative and in animals are found in various vital organs, including the anti-infective drugs and novel immunomodulatory candidates brain, the epidermis, the respiratory and gastrointestinal tracts (Luong et al., 2020; Mahlapuu et al., 2020). (Lakshmaiah Narayana and Chen, 2015). They show a different AMPs are bioactive small proteins, naturally produced by all mechanism of action than the cationic ones. In order to facilitate living organisms as important and indispensable components of their interaction with the target organism, some anionic AMPs their innate immune system, becoming the first-line defense use metal ions to form cationic salt bridges with negatively against microbial attacks in Eukaryotes, or produced as a charged constituents of microbial membranes, allowing their competition strategy in Prokaryotes, to limit the growth of penetration into the cell. When they reach the cytoplasm, they other microorganisms (Lei et al., 2019; Magana et al., 2020). may attach to ribosomes or inhibit ribonuclease activity Natural AMPs have potent and broad-spectrum activity against (Jeżowska-Bojczuk and Stokowa-Sołtys, 2018). Some anionic multiple classes of bacteria, yeasts, fungi, viruses and parasites AMPs, such as theromyzin from Theromyzon tessulatum (Huan et al., 2020; Luong et al., 2020), displaying bacteriostatic, (Tasiemski et al., 2004), require zinc as a functional cofactor microbicidal and cytolytic properties (Pasupuleti et al., 2012). and it was found that the complex with zinc has stronger Moreover, the interest in AMPs has recently increased during the antimicrobial activity (Jiang et al., 2014). Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- Despite their relative similarity in biophysical characteristics, 2) pandemic in the search of new antiviral molecules to AMP sequences are rarely similar among closely related or counteract COVID-19 disease (Kurpe et al., 2020). distinct species/organisms (Pasupuleti et al., 2012). However, AMPs were discovered in 1939, when the microbiologist René for some AMPs, a certain degree of identity is found either in the Dubos isolated from a soil Bacillus strain, an antimicrobial agent, pro-region (the inactive sequence that is deleted by post- named gramicidin, which was demonstrated to protect mice translational modifications) or in the amino acid patterns. This from pneumococcal infection (Van Epps, 2006). Afterwards, event could be due to species adaptation to the unique microbial several AMPs have been discovered from both the prokaryotic environment that characterize the niche occupied by specific and eukaryotic kingdom (Boparai and Sharma, 2020), including species (Pasupuleti et al., 2012). the tyrocidine, produced by the bacteria Bacillus brevis, with The amphiphilic nature of the majority of AMPs is activity against bacteria, and the purothionin, identified in the responsible for their structural