Genus Nocardiopsis: History
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Actinomycetes are currently one of the major sources of bioactive secondary metabolites used for medicine development. Accumulating evidence has shown that Nocardiopsis, a key class of actinomycetes, has the ability to produce novel bioactive natural products. 

  • actinomycetes
  • Nocardiopsis
  • natural products
  • bioactivities
  • medicinal potentiality

1. Introduction

Actinomycetes belong to Gram-positive bacteria and are one of the biggest bacterial phyla [1]. The high G+C DNA content of actinomycetes implied their enormous biosynthetic potential to produce various natural products with diverse structures and important commercial applications [1]. Two-thirds of all naturally derived antibiotics have been discovered from actinobacteria [1]. Approximately 70% of the pharmaceutically active natural products which are currently used in clinics are isolated from actinobacteria [2][2][3], including a series of anticancer, antifungal, antibacterial, antihelminthic, and immunosuppressive drugs [1].
Nocardiopsis is an important genus of actinobacterium for its extensive application in agriculture [3], industry , and environmental protection [4], especially for its potential ability to produce new natural products [2][4]. By mid-2021, 3% of marine actinomycetes-derived natural products were produced by Nocardiopsis, and Nocardiopsis are the third-largest actinomycetes in terms of producing marine compounds . In addition, Nocardiopsis are a prolific source of bioactive natural products in both marine and terrestrial environments and are widely distributed in multiple ecosystems [4], including deserts [5], deep ocean [5], coastal wetlands , and saline–alkali soil [6]. Nocardiopsis species have the ability to survive under different and hostile environmental conditions, mainly benefitting from their excretion of enzymes, multipurpose genetic constitution, and their ability to produce compuponible solutes and surfactants [4][6][7]. Besides these characteristics, the members of this genus have the ability to produce abundant bioactive compounds, which may allow them to prevail in different habitats [4]. Extracts from cultivated Nocardiopsis have exhibited cytotoxic [7], antimicrobial [8][8], antifibrotic , and anti-inflammatory activities. Comprehensive analyses of Nocardiopsis metabolites by LC-HRES-MS, HRMS, or GC/MS have led to the identification of bioactive and structurally diverse compounds [7][9][9]. The bioactive secondary metabolites isolated from Nocardiopsis include antimicrobial agents [10][10], tumor promoters [11], cytotoxic compounds [11], kinase and P-glycoprotein inhibitors [12][12], immunoregulators , and natural products with other multiple bioactivities [13][13]. The secondary metabolites discovered from Nocardiopsis have shown a great diversity of structural frameworks, including polyketides [14][14], alkaloids [15][15], and terpenoids [16].

2. Polyketides

Three new angucyclines, nocardiopsistins A–C (13), were obtained from the deep-sea sponge-derived Nocardiopsis sp. strain HB-J378 (Figure 1) [16]. The antibacterial activities of compounds 13 were tested against MRSA (methicillin-resistant Staphylococcus aureus) and 13 exhibited antibacterial activity with MIC values of 3.12–12.5 μg/mL. Three core genes were identified through bioinformatic analysis of the sketch genome of the strain HB-J378 in a biosynthetic gene cluster encoding a typical aromatic or type II polyketide synthase (PKS) system, including acyl carrier protein (ACP), ketoacyl: ACP synthase α-subunit (KSα) and β-subunit (KSβ). The brief biosynthetic route for 13 was proposed according to the discovered oviedomycin pathway . Compounds 13 were supposed to be biosynthesized by taking advantage of one molecule of isobutyral-CoA and nine molecules of malonyl-CoA, through complex enzymatic reactions to obtain the key angucycline biosynthetic intermediate UWM6, an analog of 13 [17], to acquire 13 (see Figure 1) [16].
Figure 1. Structural formulas and proposed biosynthesis mechanism for compounds 13 [16].
The new strain Nocardiopsis sp. CG3 (DSM 106572), collected from the saltpan of Kenadsa (22 km west of Bechar, located in southwest Algeria), was discovered to have the ability to produce new bioactive natural products in a screening program [17]. Chemical investigation of the strain led to the isolation of five new polyene macrolactams, kenalactams A−E (48) (Figure 2) [17]. The biosynthetic pathway of polyketide kenalactam A (4) was studied by feeding experiments and was found to used L-alanine as the nitrogen-bearing starter unit. Compounds 68 exhibited cytotoxic activity against HeLa (cervical cancer cells KB3.1) and PC-3 (human prostate cancer) cell lines, with IC50 values ranging from 2.1 to 6.8 μM [17].
Figure 2. Structural formulas of compounds 48 [17]. (Reprinted with permission from Ref. [17], Copyright 2019, Journal of Natural Products, published by American Chemical Society).
Eight new α-pyrone derivatives, nocahypyrones A–H (916), along with one known analog, germicidin G (17) (Figure 3) were isolated from the strains Nocardiopsis sp. HDN154-146 and HDN154-168, which were collected from soil samples derived from the Takla Makan desert area in Xinjiang Province, China. This was the first time it was reported that compounds 13 and 16 showed cytoprotective activity by inducing the expression of phase II detoxifying enzymes . Aldo-keto reductase family1 member C1 (AKR1C1), human NAD(P)H: quinone oxidoreductase 1 (NQO1), superoxide dismutase 2 (SOD2), and heme oxygenase 1(HO-1), belonging to phase II detoxifying enzymes, have been illustrated to possess significant roles in defending mammalian cells against oxidative damage and excessive inflammatory reaction [18][18]. Compounds 13 and 16 displayed cytoprotective activity by inducing the expression level of SOD2 and HO-1 in HaCaT cells .
Figure 3. Structural formulas of compounds 923 [19].
Chemical investigation of the actinobacterium Nocardiopsis sp. HDN 17-237 led to the isolation of one new β,γ-butenoate derivative, phenylbutenote (18), and one new α-pyrone, nocapyrone T (19) (Figure 3). The strain HDN 17-237 was collected from deep-sea water from the Mariana Trench (depth 4448 m, 10°21.100′ N, 142°17.574′ E, gathered in September 2016). Compounds 18 and 19 were evaluated for antibacterial and antioxidant activities, while neither of them exhibited obvious activity .
Comprehensive research of the secondary metabolites of an Antarctic marine animal sample-derived actinomycete, N. aegyptia HDN19-252, combined with a molecular networking approach in the Global Natural Products Social (GNPS) platform, obtained the isolation of four new anthraquinone derivatives, saliniquinones G−I (2022) and heraclemycin E (23) (Figure 3). Compounds 20 and 21 showed potent antibacterial activities against six evaluated bacterial strains—Bacillus subtilis, methicillin-resistant coagulase-negative staphylococci (MRCNS), B. cereus, Proteus sp., Mycobacterium phlei, and Escherichia coli—with MIC values of 3.1−12.5 µM [19].
Three new macrolides, borrelidins C−E, along with one known analog, borrelidin, which showed antibacterial and anticancer activities, were isolated from a saltern-derived halophilic Nocardiopsis sp. in 2017 . These borrelidins were found to have the ability to relieve the amyloid-β induced toxicity in the HT22 cell line in 2021, indicating the potential of borrelidins to be developed as Alzheimer’s disease drugs [19].

3. Alkaloids

The approach of an optimized nitroso-based probe (dienophile probe), promoting the detection of compounds containing conjugated alkenes in crude broth extracts, was employed in the chemical investigation of a marine-derived Nocardiopsis sp. CNY-503 and gained the isolation of one new polyketide alkaloid, named nocarditriene (24), which contained an unprecedented epoxy-2,3,4,5-tetrahydropyridine structure (Figure 4) .
Figure 4. Structural formulas of compounds 2426 [20].
The structure of nocarbenzoxazole G (25), isolated from the marine-derived actinomycete N. lucentensis DSM 44048 in 2015 [20], was revised into the nocarbenzoxazole G (26) molecule by total synthesis in 2019. The benzoxazole skeleton was constructed with microwave assistance and continued by carbon–carbon bond formation with relevant aryl bromides [20]. Compound 26 was found to display moderate cytotoxicity against HepG2 and HeLa cell lines with IC50 values of 16 and 14 μM, respectively [20].
Chemical investigation of the strain N. flavescens NA01583, which was gained from marine sediment gathered at the coast near Hainan Island in 2016 through the genome mining of an indolocarbazole-type gene cluster, led to the isolation of three new indolocarbazole alkaloids, named loonamycins A−C (2729) (Figure 5) .
Figure 5. Structural formulas of compounds 2734 [21][21].
Compound 29 was produced successfully by the allogenetic expression of the complete loo gene cluster in a vicarious host, Streptomyces lividans K4−114. The indolocarbazole skeleton of 2729, belonging to the family of indolocarbazole alkaloids, is structurally similar to that of rebeccamycin and staurosporine with an additional rare modified tryptophan ring. The molecular bases of these modifications were investigated by carefully analyzing loo BGC for further genome mining and combinational biosynthetic research. The loo gene cluster sustains a ∼36 kb continuous DNA sequence, including 25 open reading frames which take charge of biosynthesis, regulation, and resistance (Figure 6A). A possible biosynthetic pathway for loonamycin was detected based on this bioinformatic analysis (Figure 6B). In particular, compound 27 showed potent cytotoxic activities toward eight cancer cell lines, including Sum1315 (breast cancer), SH-SY5Y (neuroblastoma), HCT116 (colorectal cancer), HT29 (colorectal cancer), HCC78 (lung cancer), HeLa (cervical cancer), SW620 (colorectal cancer), and SW872 (liposarcoma), with IC50 values of 41−283 nM .
Figure 6. Biosynthesis of loonamycins: (A) loo, atm, and reb gene clusters. (B) Detected biosynthetic route for compounds 27 and 28 . (Reprinted with permission from Ref. , Copyright 2020, Organic Letters, published by American Chemical Society).
The broth culture crude extracts of actinobacterium Nocardiopsis sp. SCA30, derived from marine sediments collected from Havelock Island, Andaman, and the Nicobar Islands, India (11.96° N, 93.00° E), displayed cytotoxic activities against a series of cell lines, including HT 29, HCT 15, MDA-MB 468, and MCF 7 at concentrations ranging from 62.5 to 1000 µg/mL. The strain extracts also showed antibacterial activities against MRSA ATCC NR-46171 and NR-46071 with MIC values of 7.81 and 15.62 µg/mL, respectively. Compound 1-acetyl-4-4(hydroxyphenyl)piperazine (30) (Figure 5) was isolated from the crude extracts of Nocardiopsis sp. SCA30 through LC-MS analysis and NMR chemical structural identification approved to be an antibacterial and cytotoxic compound .
Chemical investigation of actinomycete N. dassonvillei SCSIO 40065 derived from the marine sponge Petrosia sp., which was collected on the seabed near Yongxing Island in the South China Sea at a depth of 20 m, led to the isolation of two polycyclic thioalkaloides, dassonmycins A (31) and B (32) (Figure 5). The new isolated compounds 31 and 32 contained the skeleton of a 6/6/6/6-fused tetracyclic ring featuring a naphthoquinone [2,3-e] piperazine-[1,2-c] thiomorpholine. Both compounds exhibited antibacterial activities against Micrococcus luteus SCSIO ML01, B. subtilis 1064, MRSA shhsA1, and S. aureus ATCC 29213 with MICs of 8−64 μg/mL. Compound 31 was found to display weak inhibited growth of Vibrio alginolyticus ATCC 13214 and Enterococcus faecalis ATCC 29212, with MIC values of 32 μg/mL. Compounds 31 and 32 exhibited moderate cytotoxicity against four human cancer cell lines—HepG-2, SF-268, MCF-7, and A549—with IC50 values of 12−34 μM [21]. Biosynthetically, 31 and 32 are proposed to be biosynthesized by a non-ribosomal peptide synthetase (NRPS) route combined with a chorismate pathway (Figure 7) [21].
Figure 7. Proposed biosynthesis of compounds 31 and 32 [21]. (Reprinted with permission from Ref. [21], Copyright 2021, Organic Letters, published by American Chemical Society).
A marine sediment-derived actinobacterium N. dassonvillei JS106 showed potent antiquorum sensing activities against S. aureus and Pseudomonas aeruginosa [21]. The marine sediment sample was gathered from Lianyungang, China. Secondary metabolites research of the strain JS106 led to the isolation of one new compound, 2-hydroxyacetate-3-hydroxyacetamido-phenoxazine (HHP, 33), and one known analog questiomycin A (34) (Figure 5). Both of these two compounds (33 and 34) exhibited antibiofilm activity against Chromobacterium violaceum 12472 with IC50 values of 23.59 and 6.82 μg/mL, respectively [21].

This entry is adapted from 10.3390/md20060374


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