The Ascidian-Derived Metabolites with Antimicrobial Properties
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antibiotics Review The Ascidian-Derived Metabolites with Antimicrobial Properties Marcello Casertano , Marialuisa Menna * and Concetta Imperatore Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy; [email protected] (M.C.); [email protected] (C.I.) * Correspondence: [email protected]; Tel.: +39-081678518 Received: 30 June 2020; Accepted: 11 August 2020; Published: 13 August 2020 Abstract: Among the sub-phylum of Tunicate, ascidians represent the most abundant class of marine invertebrates, with 3000 species by heterogeneous habitat, that is, from shallow water to deep sea, already reported. The chemistry of these sessile filter-feeding organisms is an attractive reservoir of varied and peculiar bioactive compounds. Most secondary metabolites isolated from ascidians stand out for their potential as putative therapeutic agents in the treatment of several illnesses like microbial infections. In this review, we present and discuss the antibacterial activity shown by the main groups of ascidian-derived products, such as sulfur-containing compounds, meroterpenes, alkaloids, peptides, furanones, and their derivatives. Moreover, the direct evidence of a symbiotic association between marine ascidians and microorganisms shed light on the real producers of many extremely potent marine natural compounds. Hence, we also report the antibacterial potential, joined to antifungal and antiviral activity, of metabolites isolated from ascidian-associate microorganisms by culture-dependent methods. Keywords: ascidian; antibacterial; antimicrobial; antiviral; marine natural products; ascidian- associated microorganisms 1. Introduction Antimicrobial agents (including antibiotic, antiviral, antifungal, and antiprotozoal drugs) certainly are critical tools for the treatment of infectious diseases, and many feats of modern medicine and surgery also are determined by the availability of effective antibiotics. Unfortunately, many microorganisms have developed several and different mechanisms of drug-resistance, mainly owing to the misuse and overdose of antimicrobial drugs. Indeed, many marketed anti-infective drugs are losing their efficacy at a rapid pace, and antimicrobial resistance has emerged as one of the major problems that the public health has had to face in the 21st century [1,2]. It has been estimated that, by the year 2050, ten million people will die per year worldwide as a direct consequence of antimicrobial resistance [3]. Resistant infections are on the rise globally, and all countries are affected. In the United States, about 3 million people get an antibiotic-resistant infection each year, with more than 35,000 deaths. On the other hand, in Europe antibiotic resistant causes ~33,000 deaths annually. As for children and neonates, they are disproportionately affected by antibiotic resistant infections, particularly in the poorest regions worldwide. For example, approximatively 30% of neonates affected by sepsis die as a result of the ineffectiveness of antibiotic treatment [2]. Thus, the need for novel antimicrobial drugs is truly great and, besides the search for vaccines as well as for novel diagnostic tools to understand the resistance mechanisms, considerable importance is given to find new chemical scaffolds for antibiotic development. However, where we can find new lead compounds with unprecedented activities? Natural products, which are the result of the countless possible interactions among the millions of diverse terrestrial and marine species existing worldwide, are evolutionarily optimized as intrinsic Antibiotics 2020, 9, 510; doi:10.3390/antibiotics9080510 www.mdpi.com/journal/antibiotics Antibiotics 2020, 9, 510 2 of 30 Antibiotics 2020, 9, x FOR PEER REVIEW 2 of 30 drug-likedrug-like moleculesmolecules andand playplay anan increasinglyincreasingly crucialcrucial rolerole inin drugdrug discoverydiscovery owingowing toto theirtheir greatgreat chemicalchemical diversity.diversity. The The wide wide chemical chemical space space occupied occupied by the secondaryby the secondary metabolites metabolites of living organisms of living andorganisms microorganisms and microorganisms is an authentic is an example authentic of how example combinatorial of how combinatorial chemistry has chemistry been performed has been by natureperformed for thousands by nature of for years, thousands giving a of real years, arsenal giving of drug a real lead arsenal candidates of drug [4]. Thelead marine candidates environment [4]. The coversmarine 71% environment of the Earth’s covers surface 71% and of comprises the Earth’s 50–80% surface of theand total comprises global biodiversity, 50–80% of whichthe total translates global intobiodiversity, an enormous which chemical translates diversity into an [enormous5]; every year, chem hundredsical diversity of novel [5]; every compounds year, hundreds are isolated of novel and identified,compounds especially are isolated from and marine identifi invertebratesed, especially [6–17 ].from In fact, marine these inve speciesrtebrates are sessile [6–17]. or slowIn fact, moving these andspecies soft are bodied; sessile although or slow they moving commonly and soft host bodi microorganisms,ed; although they they commonly lack the sophisticated host microorganisms, adaptable immunethey lack systems the sophisticated seen in vertebrates. adaptable Nevertheless, immune system theys seen thrive in and vertebrates. keep themselves Nevertheless, free of they infections, thrive whichand keep means themselves that they free rely of entirely infections, on theirwhich innate means immune that they system. rely entirely It has been on their widely innate proven immune that, assystem. a part It of has their been eff ortwidely for survival,proven that, marine as a invertebratespart of their effort have for developed survival,biosynthetic marine invertebrates pathways have for productiondeveloped biosynthetic of a wealth of pathways secondary for metabolites production to of be a usedwealth as of chemical secondary defense metabolites and communication. to be used as Inchemical this evolutionary defense and process, communication. their symbiotic In this association evolutionary with process, microorganisms their symbiotic plays aassociation key role [18 with]. microorganismsAmong the marine plays a invertebrates, key role [18]. ascidians are the most closely related to humans; they constitute the biggestAmong and the most marine varied invertebrates, class of the ascidians sub-phylum are Tunicata,the most comprisingclosely related about to 3000humans; described they speciesconstitute [19 ].the Ascidians biggest haveand most been shownvaried toclass be anof exceptionallythe sub-phylum important Tunicata, source comprising of natural about products 3000 withdescribed biomedical species and [19]. pharmaceutical Ascidians have applications, been shown especially, to be an butexceptionally not exclusively important in cancer source [10, of11 ,natural20–22]. Furthermore,products with ascidiansbiomedical harbour and pharmaceutical a great microbial applic communityations, especially, (including but no bacteria,t exclusively actinobacteria, in cancer cyanobacteria,[10,11,20–22]. Furthermore, and fungi; Figure ascidians1A), whichharbour represents a great anmicrobial additional community source of (including natural products, bacteria, manyactinobacteria, of which cyanobacteria, are extremely and potent fungi; and Figure mainly 1A), cytotoxic which represents and antimicrobial, an additional but alsosource antioxidant, of natural anti-inflammatory,products, many of andwhich many are othersextremely (Figure potent1B) and [ 23 ].mainly Indeed, cytotoxic it has beenand antimicrobial, proven that about but also 8% ofantioxidant, the bioactive anti-inflammatory, molecules isolated and from many ascidians others (Figure derive from1B) [23]. symbiotic Indeed, microorganisms; it has been proven recently, that theabout development 8% of the bioactive of culture-independent molecules isolated methods from allowed ascidians to isolatederive andfrom study symbiotic the ascidian-associated microorganisms; microorganismsrecently, the development and their of involvement culture-independent in the synthesis methods of allowed bioactive to metabolitesisolate and study isolated the fromascidian- the invertebratesassociated microorganisms [24]. and their involvement in the synthesis of bioactive metabolites isolated from the invertebrates [24]. FigureFigure 1. 1. (A(A) )Percentage Percentage distribution distribution of of microorganismsmicroorganisms pairedpaired toto ascidiansascidians from from which which marine marine B metabolitesmetabolites derive; derive; ( (B)) bioactivities ofof secondarysecondary metabolitesmetabolites isolatedisolated from from ascidian-associated ascidian-associated microorganisms described as percentage distribution. microorganisms described as percentage distribution. The aim of the present review is to focus the chemical diversity of the secondary metabolites with The aim of the present review is to focus the chemical diversity of the secondary metabolites antibacterial activity (often joint to antiviral, antifungal, or antiprotozoal effects) isolated from marine with antibacterial activity (often joint to antiviral, antifungal, or antiprotozoal effects) isolated from ascidians through January 2020. This collection shows that, so far, more than 160 substances have been marine ascidians through January 2020. This collection shows that, so far, more than 160 substances