The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms

marine drugs Review The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms 1,2, 1,2,3, , 1,2,3 1,2,3, Minghua Jiang y , Senhua Chen * y , Jing Li and Lan Liu * 1 School of Marine Sciences, Sun Yat-sen University, Guangzhou 510006, China; [email protected] (M.J.); [email protected] (J.L.) 2 South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Guangzhou 510006, China 3 Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Zhuhai 519000, China * Correspondence: [email protected] (S.C.); [email protected] (L.L.); Tel.: +86-020-84725459 (S.C. & L.L.) These authors contributed equally to this work. y Received: 25 January 2020; Accepted: 14 February 2020; Published: 15 February 2020 Abstract: Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019. Keywords: tetramic acid; bioactivity; marine natural product; marine-derived microorganisms 1. Introduction Secondary metabolites bearing a tetramic acid (pyrrolidine-2, 4-dione) motif have been isolated from various terrestrial and marine species, such as bacteria, actinobacteria, cyanobacteria, fungi, and sponges. The tetramic acid scaffold can be modified by unusual and intricate substituents to form complex, diverse chemical structures with multiple stereogenic centers. Intriguingly, an increasing number of tetramic acid products have shown a remarkable diversity of bioactivities, including antitumor, antibacterial, antifungal, and antiviral activities [1–5]. Due to their intricate structures and potent biological activity, natural tetramic acids have attracted a great deal of attention for their biosynthesis mechanisms, medicinal potential, and chemical synthesis in the biological, chemical, and pharmaceutical fields. Up to 2013, there were several reviews covering numerous aspects of naturally occurring tetramate products, such as isolation, biological activity, and synthesis, published by Royles [1], Ghisalberti [2], Gossauer [3], Schobert and Schlenk [4], and Ju et al. [5]. Many reviews have discussed the biosynthetic mechanisms of the PKS–NRPS biosynthesis pathways of tetramic acids in detail [2,5–9]. Marine natural products (MNPs) are considered an unexploited treasure trove of new bioactive NPs for the 21st century. Among them, marine microorganism-derived NPs have become the primary source of new MNPs, from less than 20% of newly discovered MNPs in 2006 to 57% in 2017 (based on a summary of a series of reviews “Marine Natural Products” published by Blunt and his colleagues during 2008–2019 [10,11]. While there have been no special reviews about tetramic acid compounds from marine microbes, especially in the past six years, numerous examples of new tetramate molecules from Mar. Drugs 2020, 18, 114; doi:10.3390/md18020114 www.mdpi.com/journal/marinedrugs Mar. Drugs 2020, 18, 114 2 of 43 Mar. Drugs 2019, 17, x 2 of 42 marine-derived microorganisms, and their related bioactivities, have been reported (up to 94 articles, 48% of thecolleagues total 195 during research 2008–2019 articles [10,11]. from While 1970–2019). there have In been the no current special review, reviews we about focus tetramic our attention acid on compounds from marine microbes, especially in the past six years, numerous examples of new the isolation, structural features, and biological activities of natural tetramate products isolated from tetramate molecules from marine-derived microorganisms, and their related bioactivities, have been marine-derivedreported (up microorganisms to 94 articles, 48% (fungi, of the actinobacteria, total 195 research bacteria, articles from and cyanobacteria)1970–2019). In the reported current up to Septemberreview, 2019. we Notably, focus our threeattention broad on the groups isolation, of compounds structural features, (cytochalasins, and biological 4-O activities-substituted of natural derivatives (i.e., tetronates),tetramate products and 2-pyridones), isolated from from marine-derived putative tetramic microorganisms acid-related (fungi, biosynthesisactinobacteria, pathwaysbacteria, have been coveredand cyanobacteria) in numerous reported reviews up [4to,6 September–8,12–16] and2019. areNotably, excluded three frombroad this groups review. of compounds (cytochalasins, 4-O-substituted derivatives (i.e., tetronates), and 2-pyridones), from putative tetramic A total of 195 research papers describing 277 tetramate compounds from marine-derived microbes acid-related biosynthesis pathways have been covered in numerous reviews [4,6–8,12–16] and are were analyzedexcluded for from this this review review. (Supplementary Table S1). The assignments of a given compound to a certain category wereA total based of on195 their research particular papers structuraldescribing features277 tetramate and biogeneticcompounds pathways. from marine-derived The compounds were characterizedmicrobes were into analyzed eight groups for this of review chemical (Suppl structures,ementary asTable shown S1). inThe Figure assignments1: simple of 3-acyl-tetramica given acids (3-ATAs),compound 3-oligoenoyltetramic to a certain category acids were (3-OTAs),based on their 3-decalinoyltetramic particular structural acids features (3-DTAs), and biogenetic 3-spirotetramic acids (3-STAs),pathways. macrocyclic The compounds tetramic were characterized acids (MTAs), into eightN-acylated groups of tetramic chemical acids,structures,α-cyclopiazonic as shown in acid Figure 1: simple 3-acyl-tetramic acids (3-ATAs), 3-oligoenoyltetramic acids (3-OTAs), 3- (CPA)-type tetramic acids, and other tetramic acids. Furthermore, the macrocyclic tetramic acids were decalinoyltetramic acids (3-DTAs), 3-spirotetramic acids (3-STAs), macrocyclic tetramic acids distributed(MTAs), into twoN-acylated subcategories: tetramic polycyclicacids, α-cyclopiazonic tetramatemacrolactams acid (CPA)-type (PTMs) tetramic from acids, marine and actinobacteria other and bacteria,tetramic and acids. pyrrocidine Furthermore, tetramate the macrocyclic alkaloids tetram (PTAs)ic acids from were marine distributed fungi. into The two piesubcategories: chart in Figure 1 providespolycyclic deeper insight tetramate into macrolactams the diversity (PTMs) and complexity from marine ofactinobacteria TAs from marine-derived and bacteria, and microbes, pyrrocidine revealing the complexitytetramate and alkaloids diversity (PTAs) of from molecules marine characterizedfungi. The pie chart as the in Figure dominating 1 provides compounds. deeper insight MTAs into (21.0%) comprisedthe diversity the largest and proportion complexity of of TAs TAs from from marine-derived marine microbes, microbes, followed revealing by theN-acylated complexity TAs and (16.0%), diversity of molecules characterized as the dominating compounds. MTAs (21.0%) comprised the 3-DTAslargest (13.0%), proportion 3-STAs of (12%), TAs from CPA-type marine TAsmicrob (9%),es, followed 3-ATAs by (9%), N-acylated and 3-OTAs TAs (16.0%), (5%). 3-DTAs As is known, structures(13.0%), can determine3-STAs (12%), properties; CPA-type TAs thus, (9%), the 3-ATAs complex (9%), and and diverse 3-OTAs structures(5%). As is known, of TAs structures will lead to the diversitycan of determine their bioactivities. properties; Therefore,thus, the complex this review and dive aimsrse tostructures give an of overview TAs will lead of the to naturallythe diversity occurring tetramateof their products bioactivities. from marine-derivedTherefore, this review microbes aims to and give their an overview biological of activities,the naturally as occurring reported in the literaturetetramate until September products from 2019, marine-derived to illustrate their microbes biodiversity, and their chemicalbiological activities, diversity, as and reported bioactive in the diversity. literature until September 2019, to illustrate their biodiversity, chemical diversity, and bioactive The origins of the strains and the diversity and biological properties of the compounds, as well as the diversity. The origins of the strains and the diversity and biological properties of the compounds, as relevantwell publication as the relevant details publication are also details summarized are also summarized (Supplementary (Supplementary Table S1). Table S1). Figure 1.FigureClassification 1. Classification of the of the 277 277 tetramic tetramic acids acids (TAs) from from marine marine microorganisms microorganisms into eight into classes. eight classes. Some examples of typical molecules belonging to these classes are illustrated: simple 3-acyl-tetramic Some examples of typical molecules belonging to these classes are illustrated: simple 3-acyl-tetramic acids (penicillenol A1), 3-oligoenoyltetramic acids (tirandamycin A), 3-decalinoyltetramic acids (equisetin), 3-spirotetramic

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