Recent advances on cyclodepsipeptides: biologically active compounds for drug research

Cyclodepsipeptides are a large family of peptide-related natural products consisting of hydroxy and amino acids linked by amide and ester bonds. A number of cyclodepsipeptides have been isolated and characterized from fungi and bacteria. Most of them showed antitumor, antifungal, antiviral, antimalarial, and antitrypanosomal properties. Herein, this review summarizes the recent literatures (2010–2022) on the progress of cyclodepsipeptides from fungi and bacteria except for those of marine origin, in order to enrich our knowledge about their structural features and biological sources.


Introduction
Cyclodepsipeptides are an important group of polypeptides, which contain one or more amino acids replaced by a hydroxy acid, resulting in at least one ester bond in the core ring structure (Lemmens-Gruber et al., 2009;Buckton et al., 2021).Cyclodepsipeptides exhibit a broad spectrum of biological activities including antitumor, antifungal, antiviral, antimalarial, and antitrypanosomal activities (Moore, 1996;Nihei et al., 1998;Du et al., 2014).Due to their unique structural and biological properties, cyclodepsipeptides have emerged as promising lead structures for crop protection and human and veterinary medicine (Sivanathan and Scherkenbeck, 2014).
The dominant sources of cyclodepsipeptides are fermentations of various fungi and bacteria.In addition, abundant cyclodepsipeptides have been isolated from algae, plants and marine organism (Sivanathan and Scherkenbeck, 2014;Negi et al., 2017).Because several reports have summarized the progress of the marine cyclodepsipeptides (Zeng et al., 2023), our review focused on the recent advances of cyclodepsipeptides from bacteria and fungi from plants, insects or soil except for marine organism.As a result, from 2010 to the present, 114 cyclodepsipeptides have been isolated and identified through an extensive literature search, including Web of Science, SciFinder, and PubChem tools.Included in the list of search terms were "cyclodepsipeptides, " "endophytic fungi, " and "insect pathogenic fungi" as well as "streptomyces, " "fungi, " "bacteria." As shown in Figure 1, the major producers of cyclodepsipeptides are endophytic fungi of plants, which made up 30.70%, followed by fungi of other origin (27.19%), streptomyces (16.67%), insect pathogenic fungi (14.04%), and other bacteria (11.40%).Liu et al. 10.3389/fmicb.2023.1276928Frontiers in Microbiology 02 frontiersin.org
In conclusion, the genus Fusarium and Trichoderma were the main producers of cyclodepsipeptides in endophytic fungi.In addition, the genus Beauveria, Sarocladium, Muscodor, Chaetomium, Phoma, Phaeosphaeria could produce diverse cyclodepsipeptides as well (Figure 4).
Verlamelins A (45) and B (46) were isolated from insect pathogenic fungus Lecanicillium sp.HF627.45 showed broad antifungal activity against plant pathogenic fungi (Ishidoh et al., 2014).Conoideocrellide A (47) was a new cyclodepsipeptide isolated from the entomopathogenic fungus Conoideocrella.tenuis BCC 18627.Unfortunately, tests showed that 47 had no biological activity in protocols for antiplasmodial and antiviral properties as well as cytotoxicity against a number of cancer cell lines (Isaka et al., 2011).The isolation of entomopathogenic fungus Percentage distribution of cyclodepsipeptides from fungi and bacteria.

Cyclodepsipeptides from streptomyces
Ulleungamides A (83) and B (84), two new cyclic depsipeptides, were found in terrestrial cultured strains Streptomyces sp.Only Staphylococcus aureus and Salmonella typhimurium showed growth inhibition by ulleungamide A (83) without cytotoxicity.Besides, Comparing 83 to 84, the selective antibacterial activity showed that the hydroxy group at position C-4 significantly lowered the activity (Son et al., 2015).Atrovimycin (85), featuring a novel vicinal-hydroxylated cinnamic acylchain, was a cyclodepsipeptide separated from Streptomyces atrovirens LQ13.A series of biological assays revealed that 85 showed a significant activity toward F. oxysporum and antitubercular activity against Mycobacterium tuberculosis H37Rv both in vitro (with MIC of 2.5 μg/mL) and in vivo (Liu et al., 2019; Figure 12).CDPs from endophytic fungi of plants.Liu et al. 10.3389/fmicb.2023.1276928Frontiers in Microbiology 06 frontiersin.orgChemical structures of CDPs 45-51.

Discussions
The chemical structures of cyclodepsipeptides, especially the absolute configurations, were complicated and difficult to determine, different methods were needed.Among them, Marfey's method, modified Mosher's method, and X-Ray diffraction analysis besides 1D-NMR and 2D-NMR (Wang et al., 2014;Liu et al., 2020;Wang et al., 2022) were the best choices for determination of the configurations for those compounds.Moreover, the MS-MS fragment analysis was also of great use for judging its sequence of the amino acids (Chung et al., 2013;Liu et al., 2020).As expected, an abundance of fungi and bacteria-derived cyclodepsipeptides were isolated, and most of them showed significant cytotoxic activities.It was suggested that the cyclic depsipeptide structure was of great importance for the biological activity, because in cytotoxicity assay, the linear homologs of the cyclohexadepsipeptide paecilodepsipeptide A were inactive (Hamann et al., 1996).In addition, the scope of bioactivity of cyclodepsipeptides spanned a range from cytotoxity, and anti-bacterial to anti-malarial activity.Thus, it was suggested that cyclodepsipeptides were desirable chemical species, and could be further applied as leading compounds in drug research.
Although most of the fungi and bacteria have been shown to be a rich source for discovering cyclodepsipeptides, the number of new cyclodepsipeptides was still limited.Conventional isolation method was time-consuming and inefficient, it was necessary to develop a more effective method to explore cyclodepsipeptide candidates.Fortunately, some studies have illustrated that the biosynthesis of cyclodepsipeptides were accomplished nonribosomally by cyclodepsipeptide synthetases (Bills et al., 2014;Du et al., 2014;Aleti et al., 2015;Liu et al., 2015), thus, targeted discovery of cyclodepsipeptides by genomic analysis became possible.By use of   Liu et al. 10.3389/fmicb.2023.1276928Frontiers in Microbiology frontiersin.orgtargeted isolation methods, such as genome mining as well as molecular networking method (Duncan et al., 2015;Paulo et al., 2019;Wei et al., 2021;Clements-Decker et al., 2022), should be paid more attention in the future in order to obtain those bioactive compounds more efficiently.
In addition, due to the small amount of cyclodepsipeptides from natural products, investigations on in vivo effects and on the detailed mechanism of the bioactivities were limited.To solve this problem, sufficient compound material was however required.Facing the problem, total synthesis and heterologous expression of genes or gene clusters in microbial hosts were two better ways, which were keys to access industrially and pharmaceutically relevant compounds in an economically affordable and sustainable manner (Stolze and Kaiser, 2013;Doi, 2014;Roderich et al., 2015).

Conclusion
In conclusion, this review gave an overview of as many as 114 natural cyclodepsipeptides isolated and identified from fungi and bacteria since 2010, among them, endophytic fungi of plant were the largest group of producers.The review enriched our knowledge about structural features of cyclodepsipeptides and their biological sources.

FIGURE 11
FIGURE 11CDPs from fungi of other origin.

TABLE 1
The inhibitory effects of CDPs on different cancer cell lines.

TABLE 2
The anti-fungal or anti-bacteria effects of CDPs.

TABLE 3
Other biological activities of CDPs.