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14 pages, 2390 KB

Open AccessEditor’s ChoiceArticle

The Discovery of Weddellamycin, a Tricyclic Polyene Macrolactam Antibiotic from an Antarctic Deep-Sea-Derived Streptomyces sp. DSS69, by Heterologous Expression

by Lu Chen, Kai Liu, Jiali Hong, Zhanzhao Cui, Weijun He, Yemin Wang, Zixin Deng and Meifeng Tao

Mar. Drugs 2024, 22(4), 189; https://doi.org/10.3390/md22040189 - 21 Apr 2024

Cited by 16 | Viewed by 4070

Abstract

Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10–0.83 μg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 μg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC₅₀ values ranging from 2.07 to 11.50 µM. Full article

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13 pages, 2795 KB

Open AccessArticle

Oxalactam A, a Novel Macrolactam with Potent Anti-Rhizoctonia solani Activity from the Endophytic Fungus Penicillium oxalicum

by Ruizhen Zhang, Yingrun Ma, Ming-Ming Xu, Xinyi Wei, Cheng-Bin Yang, Fei Zeng, Jin-Ao Duan, Chun-Tao Che, Junfei Zhou and Ming Zhao

Molecules 2022, 27(24), 8811; https://doi.org/10.3390/molecules27248811 - 12 Dec 2022

Cited by 4 | Viewed by 2921

Abstract

A novel macrolactam named oxalactam A (1), three known dipeptides (2–4) as well as other known alkaloids (5–7) were obtained from the endophytic fungus Penicillium oxalicum, which was derived from the tuber of Icacina trichantha (Icacinaceae). All chemical structures were established based on spectroscopic data, chemical methods, ECD calculations, and ¹³C-DP4+ analysis. Among them, oxalactam A (1) is a 16-membered polyenic macrolactam bearing a new skeleton of 2,9-dimethyl-azacyclohexadecane core and exhibited potent anti-Rhizoctonia solani activity with a MIC value of 10 μg/mL in vitro. The plausible biosynthetic pathway of 1 was also proposed via the alanyl protecting mechanism. Notably, three dipeptides (2–4) were first identified from the endophytic fungus P. oxalicum and the NMR data of cyclo(L-Trp-L-Glu) (2) was reported for the first time. In addition, the binding interactions between compound 1 and the sterol 14α-demethylase enzyme (CYP51) were studied by molecular docking and dynamics technologies, and the results revealed that the 16-membered polyenic macrolactam could be a promising CYP51 inhibitor to develop as a new anti-Rhizoctonia solani fungicide. Full article

(This article belongs to the Special Issue A Feasible Approach for Natural Products to Treatment of Diseases)

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34 pages, 2861 KB

Open AccessReview

Polyene Macrolactams from Marine and Terrestrial Sources: Structure, Production Strategies, Biosynthesis and Bioactivities

by Wei Zhao, Hong Jiang, Xiao-Wan Liu, Jian Zhou and Bin Wu

Mar. Drugs 2022, 20(6), 360; https://doi.org/10.3390/md20060360 - 27 May 2022

Cited by 17 | Viewed by 4337

Abstract

Over the past few decades (covering 1972 to 2022), astounding progress has been made in the elucidation of structures, bioactivities and biosynthesis of polyene macrolactams (PMLs), but they have only been partially summarized. PMLs possess a wide range of biological activities, particularly distinctive fungal inhibitory abilities, which render them a promising drug candidate. Moreover, the unique biosynthetic pathways including β-amino acid initiation and pericyclic reactions were presented in PMLs, leading to more attention from inside and outside the natural products community. According to current summation, in this review, the chem- and bio-diversity of PMLs from marine and terrestrial sources are considerably rich. A systematic, critical and comprehensive overview is in great need. This review described the PMLs’ general structural features, production strategies, biosynthetic pathways and the mechanisms of bioactivities. The challenges and opportunities for the research of PMLs are also discussed. Full article

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18 pages, 4437 KB

Open AccessArticle

Metabolic Profile, Biotransformation, Docking Studies and Molecular Dynamics Simulations of Bioactive Compounds Secreted by CG3 Strain

by Omar Messaoudi, Enge Sudarman, Chirag Patel, Mourad Bendahou and Joachim Wink

Antibiotics 2022, 11(5), 657; https://doi.org/10.3390/antibiotics11050657 - 13 May 2022

Cited by 8 | Viewed by 4465

Abstract

Actinobacteria isolated from untapped environments and exposed to extreme conditions such as saltpans are a promising source of novel bioactive compounds. These microorganisms can provide new molecules through either the biosynthetic pathway or the biotransformation of organic molecules. In the present study, we performed a chemical metabolic screening of secondary metabolites secreted by the new strain CG3, which was isolated from a saltpan located in the Sahara of Algeria, via high-performance liquid chromatography coupled with high-resolution mass spectrometry (HPLC-ESI-HRMS). The results indicated that this strain produced five new polyene macrolactams, kenalactams A–E, along with two known compounds, mitomycin C and 6″-hydroxy-4,2′,3′,4″ tetramethoxy-p-terphenyl. Furthermore, the CG3 isolate could have excellent properties for converting the aglycone isoflavone glycitein to the compounds 6,7-dimethoxy-3-(4-methoxyphenyl)chromen-4-one (50) and 6,7-dimethoxy-3-phenylchromen-4-one (54), and the isoflavone genistein can be converted to 5,7-dimethoxy-3-(4-methoxyphenyl)chromen-4-one (52). Docking studies and molecular dynamics simulations indicated that these three isoflavones, generated via biotransformation, are potent inhibitors of the target protein aromatase (CYP19A1); consequently, they can be used to prevent breast cancer risk in postmenopausal women. Full article

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12 pages, 1767 KB

Open AccessArticle

Novel Macrolactams from a Deep-Sea-Derived Streptomyces Species

by Pei Wang, Dongyang Wang, Rongxin Zhang, Yi Wang, Fandong Kong, Peng Fu and Weiming Zhu

Mar. Drugs 2021, 19(1), 13; https://doi.org/10.3390/md19010013 - 29 Dec 2020

Cited by 22 | Viewed by 5300

Abstract

Four polyene macrolactams including the previously reported niizalactam C (4), and three new ones, streptolactams A–C (1–3) with a 26-membered monocyclic, [4,6,20]-fused tricyclic and 11,23-oxygen bridged [14,16]-bicyclic skeletons, respectively, were isolated from the fermentation broth of the deep-sea sediment-derived Streptomyces sp. OUCMDZ-3159. Their structures were determined based on spectroscopic analysis, X-ray diffraction analysis, and chemical methods. The abiotic formation of compounds 2 and 4 from compound 1 were confirmed by a series of chemical reactions under heat and light conditions. Compounds 1 and 3 showed a selective antifungal activity against Candida albicans ATCC 10231. Full article

(This article belongs to the Special Issue Natural Product from the Deep Sea)

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11 pages, 1204 KB

Open AccessCommunication

Genome-Guided Discovery of Pretilactam from Actinosynnema pretiosum ATCC 31565

by Jing Wang, Xiaowen Hu, Guizhi Sun, Linli Li, Bingya Jiang, Shufen Li, Liping Bai, Hongyu Liu, Liyan Yu and Linzhuan Wu

Molecules 2019, 24(12), 2281; https://doi.org/10.3390/molecules24122281 - 19 Jun 2019

Cited by 12 | Viewed by 4526

Abstract

Actinosynnema is a small but well-known genus of actinomycetes for production of ansamitocin, the payload component of antibody-drug conjugates against cancers. However, the secondary metabolite production profile of Actinosynnema pretiosum ATCC 31565, the most famous producer of ansamitocin, has never been fully explored. Our antiSMASH analysis of the genomic DNA of Actinosynnema pretiosum ATCC 31565 revealed a NRPS–PKS gene cluster for polyene macrolactam. The gene cluster is very similar to gene clusters for mirilactam and salinilactam, two 26-membered polyene macrolactams from Actinosynnema mirum and Salinispora tropica, respectively. Guided by this bioinformatics prediction, we characterized a novel 26-membered polyene macrolactam from Actinosynnema pretiosum ATCC 31565 and designated it pretilactam. The structure of pretilactam was elucidated by a comprehensive analysis of HRMS, 1D and 2D-NMR, with absolute configuration of chiral carbons predicted bioinformatically. Pretilactam features a dihydroxy tetrahydropyran moiety, and has a hexaene unit and a diene unit as its polyene system. A preliminary antibacterial assay indicated that pretilactam is inactive against Bacillus subtilis and Candida albicans. Full article

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