Antibiotics 2022, 11, 1483. https://doi.org/10.3390/antibiotics11111483 www.mdpi.com/journal/antibiotics Review An Overview of the Potentialities of Antimicrobial Peptides Derived from Natural Sources Irene Dini 1, *, Margherita-Gabriella De Biasi 1, * and Andrea Mancusi 2 1 Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy 2 Department of Food Microbiology, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Via Salute 2, 80055 Portici, Italy * Correspondence: irdini@unina.it (I.D.); margherita.debiasi@unina.it (M.-G.D.B.) Abstract: Antimicrobial peptides (AMPs) are constituents of the innate immune system in every kind of living organism. They can act by disrupting the microbial membrane or without affecting membrane stability. Interest in these small peptides stems from the fear of antibiotics and the emergence of mi- croorganisms resistant to antibiotics. Through membrane or metabolic disruption, they defend an or- ganism against invading bacteria, viruses, protozoa, and fungi. High efficacy and specificity, low drug interaction and toxicity, thermostability, solubility in water, and biological diversity suggest their ap- plications in food, medicine, agriculture, animal husbandry, and aquaculture. Nanocarriers can be used to protect, deliver, and improve their bioavailability effectiveness. High cost of production could limit their use. This review summarizes the natural sources, structures, modes of action, and applica- tions of microbial peptides in the food and pharmaceutical industries. Any restrictions on AMPs’ large- scale production are also taken into consideration. Keywords: AMPs; food preservation; food shelf-life; active packaging; Gram-positive bacteria; Gram-negative bacteria; antibiotics; antibiotic resistance; innate immune defense molecules; mech- anism of action; delivery systems 1. Introduction Antimicrobial peptides (AMPs) are the oldest known innate immune defense mole- cules. They are abundant in plants, arthropods, microorganisms, and animals [1]. Eukar- yotes and prokaryotes synthesize AMPs in ribosomes, fungi, and bacteria, turning them into cytosol [2]. AMPs can have broad-spectrum or specific activity against pathogenic bacteria (both Gram-positive and Gram-negative), viruses, fungi, and other parasites [3]. AMPs differ in length and composition of amino acids [4]. Defensins, puroindolines, snakins, cyclotides, glycine-rich proteins, hevein, α-hairpin, knottin, and lipid transfer proteins are some natural classes of AMPs [5]. Their activity is bound by helical structure, charge, hydrophobicity, and amphipathicity [4]. The food industry employs AMPs as bi- opreservants and in food packaging (alone or with other antimicrobials and essential oils) to improve product shelf-life [6]. Antimicrobial peptides are considered potential drugs for treating infections caused by microorganisms that are untreatable with antibiotics on the market today [7,8]. They can reduce the development of antimicrobial resistance, af- fecting multiple low-affinity targets [9]. Some AMPs are subjected to peptide engineering and mutagenesis to make compounds with improved bioactivity and reduced cytotoxi- city [10,11]. This review offers an overview of structures, sources, modes of action, and applications of AMPs in the food and pharmaceutical fields. Citation: Dini, I.; De Biasi, M.; Mancusi, A. An Overview of the Potentialities of Antimicrobial Peptides Derived from Natural Sources. Antibiotics 2022, 11, 1483. https://doi.org/10.3390/ antibiotics11111483 Academic Editor: Jean-Marc Sabatier Received: 4 October 2022 Accepted: 21 October 2022 Published: 26 October 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).