Intensive and prolonged antimicrobial therapy, and the over-prescription and indiscriminate use of these drugs in veterinary medicine, have increased the resistance of microorganisms to conventional antimicrobials by selection pressure, so it is urgently necessary to search for new alternatives to these drugs. For bacteria to remain in the human organism, they have developed several defense mechanisms against antibiotics (Podschun and Ullmann, 1998). The selection pressure on susceptible microbes, the long duration and over-prescription of antimicrobial therapy and the use of various antimicrobial agents in animals raised commercially for food has made it necessary to search for new alternatives to conventional antibiotics. Thus, the types of antibiotics already commercialized and new combinations that may be available among them (Gordon et al., 2010) should be analyzed, so that they may present higher antibacterial activity against infections and biofilms (Corvec et al., 2013).

Like many living organisms, plants are constantly targets of insects, fungi and bacteria. These ongoing challenges can be responsible for the development of an efficient defense system through the synthesis of secondary metabolites such as phenols, oxygen-substituted derivatives, terpenoids, quinines, tannins, and antimicrobial peptides (AMPs) (Abreu et al., 2013). AMPs can be isolated from a wide variety of plants or parts of plants (leaves, roots, seeds, flowers, and fruits); they are considered an important part of the innate immune system and act as a complex signaling process (Maróti et al., 2011). These compounds can be classified as promiscuous proteins due to their ability to interact with several targets in Gram-positive and -negative bacteria, protozoa, yeast, fungi, and viruses (Franco, 2011). Moreover, they can also be associated in inflammatory response, infectious diseases, immunosuppressive, and tumoral diseases (Jenssen et al., 2006; Palffy et al., 2009; Rotem and Mor, 2009; Brogden and Brogden, 2011). In addition to antibiotics, environmental conditions and evolutionary pressure have made microorganisms capable of changing cellular structures or producing substances in order to contain antimicrobial peptide action (Brogden, 2005). Among the main resistance mechanisms are membrane structure modifications (Tran et al., 2006); peptide capture (Banemann et al., 1998; Friedrich et al., 1999); and capsule formation (Campos et al., 2004; Llobet et al., 2008; Jones et al., 2009; Keo et al., 2011). In this last mechanism, the capsular polysaccharide may act as a shield, blocking interaction between the cAMPs and the target cell. Capsule formation can also be performed by a dissociated polymer of P. aeruginosa, denominated an alginate, which changes the AMP's conformation, blocking its interaction with the target cell (Chan et al., 2004). Or it can be carried out by an LPS activation enzyme, which is the main component of Gram-negative cells, forming a regulatory system of PhoPQ-PmrAB and PhoP-PhoQ, so that the presence of environmental factors, such as cAMPs, can be detected in host tissues (Muhle and Tam, 2001; McPhee, 2003; Moskowitz et al., 2004; McPhee et al., 2006; Strandberg et al., 2012).

Storage organs and reproductive tissues of fruits are responsible for the production and accumulation of related peptides in the first line of defense (Tajkarimi et al., 2010; Hayek et al., 2013). They may be a source of bioactive compounds that have safer side effects when used in the prevention and control of plant pathogens and pests (Broekaert et al., 1997; Guani-Guerra et al., 2009) and of human diseases (Memarpoor-Yazdi et al., 2013). These effects can be attributed to the fact that AMPs have a mechanism of action that is significantly different from conventional antibiotics. They are natural molecules and are essential for the innate immune system (Fox, 2013). The AMPs' promising activity is due to their great applicability as antimicrobials, and they could probably be used in synergism with other drugs, creating immunomodulatory side-activities or neutralizing toxic compounds including LPS, presenting a lower minimum inhibitory concentration (MIC) than conventional antibiotics (Zasloff, 2002; Naghmouchi et al., 2012). The safer effect of AMPs may be related to their ability to act on multi-resistant microorganisms, rapidly causing the death of these pathogens and being capable of dealing with large bacterial targets (Brogden, 2005). Due to the high resistance of some infections to traditional antibiotics, AMPs with their broad spectrum antibacterial activity are highly promising in the treatment of these infections. Among them are included colistin and polymixin B, which are currently used widely in clinical practice (Falagas and Kasiakou, 2005; Zavascki et al., 2007; Landman et al., 2008). Additionally, the probability of resistance and mutagenicity being induced by AMPs may be lower in natural environments (Perron et al., 2006; Dobson et al., 2014). AMPs generated in fruits may therefore be a new target for bioprospecting new molecules with multiple targets in microorganisms and resistance frames that are relatively small compared to conventional antimicrobials (Jenssen et al., 2006). In this context, this review aims to describe the different classes of AMPs isolated from the pulp and seeds of fruit and to provide an outlook on their biotechnological potential.

AMPs are small (<10 kDa) and normally have cationic and amphipathic molecules (one surface being highly positive and the other hydrophobic and responsible for facilitating the bond between the peptide and the target membrane) (Brogden, 2005; Kang et al., 2012; Kościuczuk et al., 2012; Seo et al., 2012). These molecules can act in the cytoplasmic membrane through rupture, disintegration and formation of pores (Brogden, 2005; Nguyen et al., 2011; Li et al., 2012). In addition to the mechanisms of action related to the plasmatic membrane, cationic peptides can also act by inhibiting protein transport or enzymes (Broekaert et al., 1997; Carvalho and Gomes, 2001; Lay and Anderson, 2005), interacting with DNA, RNA, inhibiting ion channels (Kushmerick et al., 1998; Spelbrink et al., 2004), acting in the regulation of steroid hormone (Huang et al., 2013) and development of potential redox (Takayama et al., 2001; Stotz et al., 2009; Amien et al., 2010), and inhibiting peptidoglycan synthesis (Yeaman and Yount, 2003).

AMPs have been grouped into various families by the APD3 database (http://aps.unmc.edu/AP/main.php), so they can be divided, based on 3D structures, into (Wang et al., 2016): (I) linear -helical peptides; (II) cyclic peptides with β-sheet structures with two or more disulfide bonds; (III) a combination of α-helices and β-sheets stabilized by disulfide bonds; (IV) peptides with -hairpin or looped arrangement containing disulfide bonds; (V) linear peptides with an unusual predisposition for the particular repetition of some amino acid residues, including proline, glycine, tryptophan, or histidine; and (VI) short peptides with coil structures or with no defined secondary structures. Additionally to this classification, several classes of plant AMPs can also be divided by properties, such as covalent bonding patterns, hydrophobicity, net charge, or molecular targets (Wang, 2015). Among several different plant AMP classes, in fruits it is possible to detect (I) defensins (Meyer et al., 1996; Guzmán-Rodríguez et al., 2013; Seo et al., 2014), (II) lipid transfer proteins (LTPs) (Zottich et al., 2011), (III) glycine rich protein (Pelegrini et al., 2008), (IV) 2S albumin (Pelegrini et al., 2006; Ribeiro et al., 2011), (V) snakin (Daneshmand et al., 2013), (VI) napin (Da Silva Dantas et al., 2014), and (VII) and other fruit AMPs (Table 1).

The discovery of new groups of AMPs from fruit could provide a novel source of drug generation for the treatment of human infectious diseases (De Lucca, 2000; Hancock, 2000; Welling et al., 2000). In addition, the wide spectrum of antimicrobial activities in some molecules suggests they can have the potential for treating different types of cancer (Tanaka, 2001) as well as viral or parasitic infections (Wong et al., 2010).

According to a study performed by Hancock (2000), research with AMPs has been carried out for several years, demonstrating the important biotechnological development and its relevant therapeutic application, from topical administration to the systemic treatment of infections. Increasingly, AMPs are being consolidated as a new class of antibiotics, due to their broad mechanism of action, including against multi-resistant microorganisms.

AMPs act as a defense mechanism for living organisms, a fact that makes them a promising candidate for new antibiotic substances (Mansour et al., 2014). Still, it is expected that in a short time the defensins used in agro-products with antifungal activity will be used as an important instrument for the growth of agricultural production, a fact that should stimulate biotechnological research and the application of bioproducts (Lacerda et al., 2014).

AMPs with anti-infective activities have been developed in order to investigate their antimicrobial mechanisms, and it has been demonstrated that most AMPs act by interacting with the pathogen membrane (Harris et al., 2009; Lee and Lee, 2015; Dutta and Das, 2016; Lee et al., 2016). Chemical combination and modifications in targeted peptide residues are other options that can improve AMPs bioactivity, together with the use of biotechnology for the production of newly designed peptides in host plants or as biocontrol agents and for healthcare (López-García et al., 2000).

In the course of centuries, plants have been studied and serve as a major source of natural products and drugs. About half of the pharmaceutical products in use today are derived from natural products (Clark, 1996). Besides their therapeutic prospects, AMPs can be applied in the development of transgenic crops, decreasing the need for large quantities of pesticide in agriculture (Pelegrini and Franco, 2005). They have potential for conservation in the food industry (Yazdi et al., 2013) and in agribusiness (Meyer et al., 1996; Agizzio et al., 2003; Pelegrini et al., 2006, 2008; Ribeiro et al., 2011; Seo et al., 2014). Their medical use is likely to increase as anti-infective and immunomodulatory therapeutics (Matsuzaki, 1999; Mandal et al., 2009; Maróti et al., 2011; Silva et al., 2012, 2014; Jeong et al., 2015; Santana et al., 2015), in intracellular drug delivery, RNA, DNA, and nanoparticles in a non-destructive manner (Nasrollahi et al., 2012) (Figure 2).

Plant peptide screening has also introduced a new model to be applied to the development of crops resistant to pathogenic microorganisms, being of great interest in agribusiness (de Sousa Cândido et al., 2014). Moreover, the use of these molecules has effective fungicide action, besides producing lower impact on the environment compared to agrochemicals (Parachin and Franco, 2014). In this review, we have highlighted several studies regarding the antifungal properties of peptides isolated from fruits including J1, with action against F. oxysporum, B. cinerea, and C. gloeosporioides (Meyer et al., 1996; Seo et al., 2014); Pa-AFP1 against C. gloesporioides (Ribeiro et al., 2011); Pe-AFP1 against T. harzianum, A. fumigatus, and F. oxysporum (Pelegrini et al., 2006); Pf2 against F. oxysporum, C. musae, S. cerevisiae, and C. lindemuthianum (Agizzio et al., 2003); and Pg-AMP against T. harzianum, A. fumigatus, F. oxysporum, and R. solani (Pelegrini et al., 2008).

Zainal et al. (2009) showed heterologous expression strategies of peptides in plants, and the isolation of these molecules from their natural source is presented as a strategy for AMP production. The expression of chili (C. annuum) defensins in tomatoes increased the tomato plant's resistance to Fusarium sp. and Phytophthora infestans, showing that transgenic lines could be more resistant to infection by these pathogens (Zainal et al., 2009). Moreover, some studies have demonstrated that transgenic expression of plant defensins leads to protection of vegetative tissues against pathogen attack, as is the case of Fusarium-resistant tomatoes expressing the MsDef1 defensin gene (Thomma et al., 2002; Abdallah et al., 2010). For example, the rice chitinase gene (CHI), the alfalfa defensin gene (alfAFP), and their bivalent gene (CHI-AFP) (Chen et al., 2009) and the tobacco β-1,3-glucanase gene (GLU), alfalfa defensin gene alfAFP, and their bivalent gene GLU-AFP (Chen et al., 2006) were introduced into tomato line Micro-Tom via Agrobacterium-mediated gene transfer method. Besides these studies, overexpressing the defensin genes MsDef1 Medicago sativa in crops of tomatoes proved that transgenic tomato lines exhibited higher resistance and dosage-effect to B. cinerea, Ralstonia solanacearum, and F. oxysporum f. Lycopersici sp. than that of non-transgenic plants (Abdallah et al., 2010). The floral defensin genes such as PhDef1, PhDef2, Sm-AMP-D1, and DmAMP1 were overexpressing in transgenic banana (Ghag et al., 2012, 2014) and papaya (Zhu et al., 2007) plants. These genes can improve resistance to phytopathogens such as F. oxysporum f. sp. cubense and Phytophthora palmivora when compared to untransformed control plants. Transformation with the defensin gene caused the reduced thickness of the hyphae cell wall of fungi in bioassays in vitro and in situ (Zhu et al., 2007). The presence of small defensin-like sequence genes (DEFL) in the grapevine genome can inhibit conidial germination of B. cinerea in this fruit (Giacomelli et al., 2012).

In addition to the promising application of these molecules in the development of innovative approaches in agriculture, we can see their future application in medicine, contributing to the improvement of biotechnological processes (Montesinos, 2007; Holaskova et al., 2015). According to Dutta and Das (2016), it is argued that resistance to AMPs is unlikely to resemble that found regarding conventional drugs. Hence, AMPs are a promising alternative in medicine. In order to elaborate and develop AMPs, making drugs with anti-infectious potential, there has been ample observation about their vast range of mechanisms of antimicrobial action, and of the way in which the interaction with the target membrane occurs in all mechanisms (Harris et al., 2009; Lee and Lee, 2015; Dutta and Das, 2016; Lee et al., 2016). However, there is still a need for more detailed studies, including in vivo studies using isolated plant molecules (Uhliga et al., 2014), due to certain pharmacological limitations and studies related to sensitivity, generating conflicting clinical analyses (Falagas and Kasiakou, 2005; Zavascki et al., 2007; Landman et al., 2008). However, the preparation of peptides with antibacterial activity is extremely expensive, which certainly makes clinical applicability difficult (Marr et al., 2006).

Plant AMPs have also been described as potential molecules in healthcare, being considered promising as therapeutic agents, and can be used as analogous peptides, thus boosting their therapeutic activity (Asthana et al., 2004; Sun et al., 2005). It has been proposed that plant AMPs, based on their broad-spectrum activity and efficiency, may offer a good alternative for the treatment of infections in relation to conventional antibiotics (da Silva and Machado, 2012). Some studies have shown the presence of different AMPs in fruits of Capsicum (Liu et al., 2006; Taveira et al., 2014) and avocado fruit (PaDef), presenting antimicrobial activities that could be used in the treatment of infectious diseases caused by E. coli and S. aureus strains (Guzmán-Rodríguez et al., 2013). Moreover, the peptide CaThi associated with fluconazole showed inhibitory activities toward C. albicans, C. tropicalis, C. parapsilosis, C. pelliculosa, C. buinensis, and C. mogii (Taveira et al., 2016). Furthermore, it has been shown that plant AMPs cause an inhibitory effect on biofilm formation (Mandal et al., 2011), revealing that fruits could be excellent sources of bioactive molecules with promising health benefits (Skinner and Hunter, 2013).

Interestingly, an increasing number of works have labeled plant AMPs as promiscuous peptides, due to their different actions associated with the same structure (Franco, 2011). Among these are the peptide Cn-AMP1, considered multifunctional and promiscuous, presenting antibacterial and antifungal activity, also being capable to reduce the viability of tumor cells (Mandal et al., 2009; Silva et al., 2012; Santana et al., 2015). Another example is the peptides isolated from Z. jujuba fruits, with both antibacterial and antifungal properties against S. aureus and Phomopsis azadirachtae, respectively (Daneshmand et al., 2013). Extracts from fruits have also shown other activities, among these being antioxidant activity in the extract purified from Z. jujuba, which showed that some fractions can prevent oxidative reactions and are underutilized for preserving food and medicinal purposes (Yazdi et al., 2013). In addition, Litsea japônica fruits have been studied, showing that their extract can perform several activities, such as anti-osteoarthritis (Jeong et al., 2015) and activation of tumor necrosis factor-α (TNF-α) (Won et al., 2016).

Indeed, the study and description of new AMPs stemming from different parts of plants has proved to be a source of biotech products, investment in genetic engineering for the expression of these molecules, transgenic products already resistant to pathogens or production of insecticides in agriculture.

In summary, the identification and isolation of various classes of peptides examined in this review details the importance of the antimicrobial activities found in these peptides from the seeds and pulp of fruits. They present promising applicability in the search for new medicines for human health, for ways to curb the spread of pests and for increasing production of fruits for agribusiness.

BM from Universidade Católica Dom Bosco, Campo Grande–MS, Brazil, was responsible to write the topics Abstract and Fruit Antimicrobial Peptides Tables, furthermore contributes data to be inserted into the table. LM from Universidade Católica Dom Bosco, Campo Grande–MS, Brazil, contributed in Title, Abstract, Fruit Antimicrobial Peptides, Conclusion/outlooks and dates to insert into the table. KO from Universidade Católica Dom Bosco, Campo Grande–MS, Brazil was responsible to write the topic Biotechnological Potential and Figures. MN from Universidade Católica Dom Bosco, Campo Grande–MS, Brazil was responsible to write topic Fruit Antimicrobial Peptides and References formation. CC from Universidade Católica Dom Bosco, Campo Grande–MS, Brazil was responsible for the corrections of the manuscript. OF from Universidade Católica Dom Bosco, Campo Grande–MS, Brazil was responsible for the corrections of the manuscript.