Pub Date : 2024-07-03DOI: 10.1021/acs.jnatprod.4c00209
Thilini Peramuna, Caroline M Kim, Laarni Kendra T Aguila, Karen L Wendt, Gwendolyn E Wood, Robert H Cichewicz
Mycoplasma genitalium is a sexually transmitted bacterium associated with urogenital disease syndromes in the US and worldwide. The global rise in drug resistance in M. genitalium necessitates the development of novel drugs to treat this pathogen. To address this need, we have screened extracts from a library of fungal isolates assembled through the University of Oklahoma Citizen Science Soil Collection Program. Analysis of one of the bioactive extracts using bioassay-guided fractionation led to the purification of the compound PF1140 (1) along with a new and several other known pyridones. The N-hydroxy pyridones are generally regarded as siderophores with high binding affinity for iron(III) under physiological conditions. Results from UV-vis absorption spectroscopy-based titration experiments revealed that 1 complexes with Fe3+. As M. genitalium does not utilize iron, we propose that the PF1140-iron complex induces cytotoxicity by facilitating the cellular uptake of iron, which reacts with endogenous hydrogen peroxide to produce toxic hydroxyl radicals.
生殖器支原体是一种性传播细菌,在美国和全世界都与泌尿生殖系统疾病综合征有关。生殖器支原体的耐药性在全球范围内呈上升趋势,因此有必要开发治疗这种病原体的新型药物。为了满足这一需求,我们对通过俄克拉荷马大学公民科学土壤收集计划收集的真菌分离物库中的提取物进行了筛选。使用生物测定指导分馏法对其中一种具有生物活性的提取物进行分析,最终纯化出了化合物 PF1140 (1),以及一种新的和其他几种已知的吡啶酮类化合物。在生理条件下,N-羟基吡啶酮通常被认为是对铁(III)具有高结合亲和力的苷元。基于紫外可见吸收光谱的滴定实验结果表明,1 与 Fe3+ 发生络合。由于 M. genitalium 不利用铁,我们认为 PF1140-铁复合物是通过促进细胞对铁的吸收来诱导细胞毒性的,铁与内源性过氧化氢反应产生有毒的羟自由基。
{"title":"Iron(III) Binding Properties of PF1140, a Fungal <i>N</i>-Hydroxypyridone, and Activity against <i>Mycoplasma genitalium</i>.","authors":"Thilini Peramuna, Caroline M Kim, Laarni Kendra T Aguila, Karen L Wendt, Gwendolyn E Wood, Robert H Cichewicz","doi":"10.1021/acs.jnatprod.4c00209","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00209","url":null,"abstract":"<p><p><i>Mycoplasma genitalium</i> is a sexually transmitted bacterium associated with urogenital disease syndromes in the US and worldwide. The global rise in drug resistance in <i>M. genitalium</i> necessitates the development of novel drugs to treat this pathogen. To address this need, we have screened extracts from a library of fungal isolates assembled through the University of Oklahoma Citizen Science Soil Collection Program. Analysis of one of the bioactive extracts using bioassay-guided fractionation led to the purification of the compound PF1140 (<b>1</b>) along with a new and several other known pyridones. The <i>N</i>-hydroxy pyridones are generally regarded as siderophores with high binding affinity for iron(III) under physiological conditions. Results from UV-vis absorption spectroscopy-based titration experiments revealed that <b>1</b> complexes with Fe<sup>3+</sup>. As <i>M. genitalium</i> does not utilize iron, we propose that the PF1140-iron complex induces cytotoxicity by facilitating the cellular uptake of iron, which reacts with endogenous hydrogen peroxide to produce toxic hydroxyl radicals.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1021/acs.jnatprod.3c01231
Xiaoyan Chen, Bo Li
Combination therapy is an effective strategy to combat antibiotic resistance. Multiple synergistic antimicrobial combinations are produced by enzymes encoded in biosynthetic gene clusters (BGCs) that co-localize on the bacterial genome. This phenomenon led to the hypothesis that mining co-localized BGCs will reveal new synergistic combinations of natural products. Here, we bioinformatically identified 38 pairs of co-localized BGCs, which we predict to produce natural products that are related to known compounds, including polycyclic tetramate macrolactams (PoTeMs). We further showed that ikarugamycin, a PoTeM, increases the membrane permeability of Acinetobacter baumannii and Staphylococcus aureus, which suggests that ikarugamycin might be an adjuvant that facilitates the entry of other natural products. Our work outlines a promising avenue to discover synergistic combinations of natural products by mining bacterial genomes.
{"title":"Analysis of Co-localized Biosynthetic Gene Clusters Identifies a Membrane-Permeabilizing Natural Product.","authors":"Xiaoyan Chen, Bo Li","doi":"10.1021/acs.jnatprod.3c01231","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.3c01231","url":null,"abstract":"<p><p>Combination therapy is an effective strategy to combat antibiotic resistance. Multiple synergistic antimicrobial combinations are produced by enzymes encoded in biosynthetic gene clusters (BGCs) that co-localize on the bacterial genome. This phenomenon led to the hypothesis that mining co-localized BGCs will reveal new synergistic combinations of natural products. Here, we bioinformatically identified 38 pairs of co-localized BGCs, which we predict to produce natural products that are related to known compounds, including polycyclic tetramate macrolactams (PoTeMs). We further showed that ikarugamycin, a PoTeM, increases the membrane permeability of <i>Acinetobacter baumannii</i> and <i>Staphylococcus aureus</i>, which suggests that ikarugamycin might be an adjuvant that facilitates the entry of other natural products. Our work outlines a promising avenue to discover synergistic combinations of natural products by mining bacterial genomes.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ten undocumented carbazole derivatives (2-11) along with the reported analogue (1) were isolated from the mangrove-derived Streptomyces sp. OUCMDZ-5511, cultured with NaBr-supplemented liquid medium. Compounds 1-7 are brominated carbazoles, and 8, 10, and 11 feature an additional thiazole or 2,3-dihydro-1,4-oxathiine rings, respectively. Their structures were identified through spectroscopic techniques, computational chemistry, and X-ray crystallography. Notably, compounds 6 and 8 effectively inhibited immune cell migration, indicating anti-inflammatory activity in vivo, potentially via Myd88/Nf-κB pathways, as suggested for compound 6.
{"title":"Bromine/Sulfur-Substituted 9<i>H</i>-Carbazoles Produced by the Marine-Derived <i>Streptomyces</i> sp. OUCMDZ-5511 upon NaBr Exposure.","authors":"Pengcheng Yan, Jibin Liu, Kaixuan Li, Peipei Liu, Ning Li, Weiming Zhu","doi":"10.1021/acs.jnatprod.4c00317","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00317","url":null,"abstract":"<p><p>Ten undocumented carbazole derivatives (<b>2</b>-<b>11</b>) along with the reported analogue (<b>1</b>) were isolated from the mangrove-derived <i>Streptomyces</i> sp. OUCMDZ-5511, cultured with NaBr-supplemented liquid medium. Compounds <b>1</b>-<b>7</b> are brominated carbazoles, and <b>8</b>, <b>10</b>, and <b>11</b> feature an additional thiazole or 2,3-dihydro-1,4-oxathiine rings, respectively. Their structures were identified through spectroscopic techniques, computational chemistry, and X-ray crystallography. Notably, compounds <b>6</b> and <b>8</b> effectively inhibited immune cell migration, indicating anti-inflammatory activity <i>in vivo</i>, potentially via Myd88/Nf-κB pathways, as suggested for compound <b>6</b>.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1021/acs.jnatprod.4c00252
Ju Ryeong Lee, Su Jung Hwang, Yukyung Choi, Jonghwan Kim, Gyu Sung Lee, Bum Soo Lee, Ki Hyun Kim, Kyo Bin Kang, Hyo-Jong Lee, Chung Sub Kim
A family of pyrazinone metabolites (1-11) were characterized from Staphylococcus xylosus ATCC 29971. Six of them were hydroxylated or methoxylated, which were proposed to be produced by the rare noncatalytic oxa-Michael addition reaction with a water or methanol molecule. It was confirmed that isopropyl alcohol can also be the Michael donor of the reaction. 1-7 and the synthetic precursor 2a showed significant inhibition of breast cancer cell migration.
{"title":"Structural Diversification of Pyrazinone Metabolites via Spontaneous Oxa-Michael Addition in <i>Staphylococcus xylosus</i>.","authors":"Ju Ryeong Lee, Su Jung Hwang, Yukyung Choi, Jonghwan Kim, Gyu Sung Lee, Bum Soo Lee, Ki Hyun Kim, Kyo Bin Kang, Hyo-Jong Lee, Chung Sub Kim","doi":"10.1021/acs.jnatprod.4c00252","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00252","url":null,"abstract":"<p><p>A family of pyrazinone metabolites (<b>1</b>-<b>11</b>) were characterized from <i>Staphylococcus xylosus</i> ATCC 29971. Six of them were hydroxylated or methoxylated, which were proposed to be produced by the rare noncatalytic oxa-Michael addition reaction with a water or methanol molecule. It was confirmed that isopropyl alcohol can also be the Michael donor of the reaction. <b>1</b>-<b>7</b> and the synthetic precursor <b>2a</b> showed significant inhibition of breast cancer cell migration.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 μM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.
{"title":"Discovery of Oxidized <i>p</i>-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.","authors":"Jian Cai, Qian Zhou, Xin Qi, Furong Zhang, Jiafan Yang, Chunmei Chen, Kai Zhang, Zhexin Chen, Hai-Bin Luo, Yonghong Liu, Yi-You Huang, Xuefeng Zhou","doi":"10.1021/acs.jnatprod.4c00422","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00422","url":null,"abstract":"<p><p>Four new <i>p</i>-terphenyl derivatives, talaroterphenyls A-D (<b>1</b>-<b>4</b>), together with three biosynthetically related known ones (<b>5</b>-<b>7</b>), were obtained from the mangrove sediment-derived <i>Talaromyces</i> sp. SCSIO 41412. Compounds <b>1</b>-<b>3</b> are rare <i>p</i>-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that <b>1</b>-<b>7</b> were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (<i>ttpB</i>-<i>ttpE</i>). These <i>p</i>-terphenyls (<b>1</b>-<b>7</b>) and 36 marine-derived terphenyl analogues (<b>8</b>-<b>43</b>) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and <b>1</b>-<b>5</b>, <b>14</b>, <b>17</b>, <b>23</b>, and <b>26</b> showed notable activities with IC<sub>50</sub> values of 0.40-16 μM. The binding pattern of <i>p</i>-terphenyl inhibitors <b>1</b>-<b>3</b> with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (<b>1</b>), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, <b>1</b> could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized <i>p</i>-terphenyl <b>1</b>, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1021/acs.jnatprod.3c01234
Zacharie A Maw, Alyssa L Grunwald, Bradley A Haltli, Christopher Cartmell, Russell G Kerr
The marine tunicate-derived Streptomyces albidoflavus RKJM0023 was cultured in the presence of a rhamnolipid mixture in an effort to elicit the production of silent natural products. MS/MS-based molecular networking analysis enhanced with nonparametric statistics highlighted the upregulation of a molecular cluster (Kruskal-Wallis p = 1.6 e-6 for 1) in which no MS/MS features had library matches. Targeted isolation of these features resulted in the discovery of nine new N-acylated lipopeptides, albubactins A-H (1-8) each containing a unique glutamine tripeptide and a C-terminal ethyl ester moiety. Three related albubactin acids A-C (9-11) lacking the ethyl ester were also identified. NMR spectroscopy and UPLC-HR-ESI-MS/MS demonstrated that the albubactins were obtained as mixtures that shared a common m/z and differed only in their acylated terminal groups. Due to the complex spectroscopic elucidation with many overlapping shifts, a total synthesis of albubactin A (1) was completed and used to determine the absolute configuration of the new albubactins.
在鼠李糖脂混合物存在的情况下培养海洋单胞菌白化链霉菌 RKJM0023,试图诱导其产生无声天然产物。基于 MS/MS 的分子网络分析经非参数统计增强后,突出显示了一个分子集群的上调(Kruskal-Wallis p = 1.6 e-6 for 1),其中没有任何 MS/MS 特征与文库匹配。通过有针对性地分离这些特征,发现了九种新的 N-酰化脂肽,即 albubactins A-H(1-8),每种都含有独特的谷氨酰胺三肽和 C 端乙酯分子。此外,还发现了三种缺乏乙酯的相关白桦脂酸 A-C(9-11)。核磁共振光谱和 UPLC-HR-ESI-MS/MS 显示,这些白桦酯以混合物的形式存在,它们的 m/z 值相同,只是酰化末端基团不同。由于复杂的光谱分析存在许多重叠的位移,因此完成了白桦脂素 A(1)的全合成,并用于确定新白桦脂素的绝对构型。
{"title":"Discovery of the Lipopeptides Albubactins A-H from <i>Streptomyces albidoflavus</i> RKJM0023 via Chemical Elicitation with Rhamnolipids and Synthesis of Albubactin A.","authors":"Zacharie A Maw, Alyssa L Grunwald, Bradley A Haltli, Christopher Cartmell, Russell G Kerr","doi":"10.1021/acs.jnatprod.3c01234","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.3c01234","url":null,"abstract":"<p><p>The marine tunicate-derived <i>Streptomyces albidoflavus</i> RKJM0023 was cultured in the presence of a rhamnolipid mixture in an effort to elicit the production of silent natural products. MS/MS-based molecular networking analysis enhanced with nonparametric statistics highlighted the upregulation of a molecular cluster (Kruskal-Wallis <i>p</i> = 1.6 e<sup>-6</sup> for <b>1</b>) in which no MS/MS features had library matches. Targeted isolation of these features resulted in the discovery of nine new <i>N-</i>acylated lipopeptides, albubactins A-H (<b>1</b>-<b>8</b>) each containing a unique glutamine tripeptide and a <i>C</i>-terminal ethyl ester moiety. Three related albubactin acids A-C (<b>9</b>-<b>11</b>) lacking the ethyl ester were also identified. NMR spectroscopy and UPLC-HR-ESI-MS/MS demonstrated that the albubactins were obtained as mixtures that shared a common <i>m</i>/<i>z</i> and differed only in their acylated terminal groups. Due to the complex spectroscopic elucidation with many overlapping shifts, a total synthesis of albubactin A (<b>1</b>) was completed and used to determine the absolute configuration of the new albubactins.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-21DOI: 10.1021/acs.jnatprod.4c00445
Diana A Barrera-Adame, Sabine Schuster, Timo H J Niedermeyer
Specialized metabolites play important roles in plants and can, for example, protect plants from predators or pathogens. Alkaloids, due to their pronounced biological activity on higher animals, are one of the most intriguing groups of specialized metabolites, and many of them are known as plant defense compounds. Poison hemlock, Conium maculatum, is well-known for its high content of piperidine alkaloids, of which coniine is the most famous. The distribution, localization, and diversity of these compounds in C. maculatum tissues have not yet been studied in detail. The hemlock alkaloids are low molecular weight compounds with relatively high volatility. They are thus difficult to analyze on-tissue by MALDI mass spectrometry imaging due to delocalization, which occurs even when using an atmospheric pressure ion source. In this manuscript, we describe an on-tissue derivatization method that allows the subsequent determination of the spatial distribution of hemlock alkaloids in different plant tissues by mass spectrometry imaging. Coniferyl aldehyde was found to be a suitable reagent for derivatization of the secondary amine alkaloids. The imaging analysis revealed that even chemically closely related hemlock alkaloids are discretely distributed in different plant tissues. Additionally, we detected a yet undescribed hemlock alkaloid in Conium maculatum seeds.
{"title":"Mass Spectrometry Imaging of Coniine and Other Hemlock Alkaloids after On-Tissue Derivatization Reveals Distinct Alkaloid Distributions in the Plant.","authors":"Diana A Barrera-Adame, Sabine Schuster, Timo H J Niedermeyer","doi":"10.1021/acs.jnatprod.4c00445","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00445","url":null,"abstract":"<p><p>Specialized metabolites play important roles in plants and can, for example, protect plants from predators or pathogens. Alkaloids, due to their pronounced biological activity on higher animals, are one of the most intriguing groups of specialized metabolites, and many of them are known as plant defense compounds. Poison hemlock, <i>Conium maculatum</i>, is well-known for its high content of piperidine alkaloids, of which coniine is the most famous. The distribution, localization, and diversity of these compounds in <i>C. maculatum</i> tissues have not yet been studied in detail. The hemlock alkaloids are low molecular weight compounds with relatively high volatility. They are thus difficult to analyze on-tissue by MALDI mass spectrometry imaging due to delocalization, which occurs even when using an atmospheric pressure ion source. In this manuscript, we describe an on-tissue derivatization method that allows the subsequent determination of the spatial distribution of hemlock alkaloids in different plant tissues by mass spectrometry imaging. Coniferyl aldehyde was found to be a suitable reagent for derivatization of the secondary amine alkaloids. The imaging analysis revealed that even chemically closely related hemlock alkaloids are discretely distributed in different plant tissues. Additionally, we detected a yet undescribed hemlock alkaloid in <i>Conium maculatum</i> seeds.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 10.1021/acs.jnatprod.4c00184
Natalia L Cancelarich, Miriam Arrulo, Sariah Trillo Gugliotti, Eder A Barbosa, Daniel C Moreira, Néstor G Basso, Luis Orlando Pérez, Cátia Teixeira, Paula Gomes, Beatriz G de la Torre, Fernando Albericio, Peter Eaton, José R S A Leite, Mariela M Marani
The adaptation of amphibians to diverse environments is closely related to the characteristics of their skin. The complex glandular system of frog skin plays a pivotal role in enabling these animals to thrive in both aquatic and terrestrial habitats and consists of crucial functions such as respiration and water balance as well as serving as a defensive barrier due to the secretion of bioactive compounds. We herein report the first investigation on the skin secretion of Odontophrynus americanus, as a potential source of bioactive peptides and also as an indicator of its evolutionary adaptations to changing environments. Americanin-1 was isolated and identified as a neutral peptide exhibiting moderate antibacterial activity against E. coli. Its amphipathic sequence including 19 amino acids and showing a propensity for α-helix structure is discussed. Comparisons of the histomorphology of the skin of O. americanus with other previously documented species within the same genus revealed distinctive features in the Patagonian specimen, differing from conspecifics from other Argentine provinces. The presence of the Eberth-Katschenko layer, a prevalence of iridophores, and the existence of glycoconjugates in its serous glands suggest that the integument is adapted to retain skin moisture. This adaptation is consistent with the prevailing aridity of its native habitat.
{"title":"First Bioprospecting Study of Skin Host-Defense Peptides in <i>Odontophrynus americanus</i>.","authors":"Natalia L Cancelarich, Miriam Arrulo, Sariah Trillo Gugliotti, Eder A Barbosa, Daniel C Moreira, Néstor G Basso, Luis Orlando Pérez, Cátia Teixeira, Paula Gomes, Beatriz G de la Torre, Fernando Albericio, Peter Eaton, José R S A Leite, Mariela M Marani","doi":"10.1021/acs.jnatprod.4c00184","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00184","url":null,"abstract":"<p><p>The adaptation of amphibians to diverse environments is closely related to the characteristics of their skin. The complex glandular system of frog skin plays a pivotal role in enabling these animals to thrive in both aquatic and terrestrial habitats and consists of crucial functions such as respiration and water balance as well as serving as a defensive barrier due to the secretion of bioactive compounds. We herein report the first investigation on the skin secretion of <i>Odontophrynus americanus</i>, as a potential source of bioactive peptides and also as an indicator of its evolutionary adaptations to changing environments. Americanin-1 was isolated and identified as a neutral peptide exhibiting moderate antibacterial activity against <i>E. coli</i>. Its amphipathic sequence including 19 amino acids and showing a propensity for α-helix structure is discussed. Comparisons of the histomorphology of the skin of <i>O. americanus</i> with other previously documented species within the same genus revealed distinctive features in the Patagonian specimen, differing from conspecifics from other Argentine provinces. The presence of the Eberth-Katschenko layer, a prevalence of iridophores, and the existence of glycoconjugates in its serous glands suggest that the integument is adapted to retain skin moisture. This adaptation is consistent with the prevailing aridity of its native habitat.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1021/acs.jnatprod.4c00215
Jian-Zi Liu, Yan-Duo Wang, Hui-Qi Fang, Gui-Bo Sun* and Gang Ding*,
Chetocochliodin M (5) containing a rare cage-ring and chetocochliodin N (6) featuring an unusual piperazine-2,3-dione ring system together with known analogues chetomin (1), chetoseminudin C (2), chetocochliodin I (3), and oidioperazine E (4) were targeted for purification from the fungus Chaetomium cochliodes using a UPLC-Q-TOF-MS/MS approach. The structures of the new compounds were elucidated using HR-ESI-MS, NMR, and ECD spectra. Compounds 1, 3, and 6 exhibited strong cytotoxic activities against A549 and HeLa cancer cell lines.
采用 UPLC-Q-TOF-MS/MS 方法,从真菌 Chaetomium cochliodes 中纯化了含有罕见笼环的 Chetocochliodin J (5) 和具有不寻常哌嗪-2,3-二酮环系的 Chetocochliodin K (6),以及已知的类似物 chetomin (1)、chetoseminudin C (2)、chetocochliodin I (3) 和 oidioperazine E (4)。利用 HR-ESI-MS、NMR 和 ECD 光谱阐明了新化合物的结构。化合物 1、3 和 6 对 A549 和 HeLa 癌细胞株具有很强的细胞毒活性。
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Pub Date : 2024-06-18DOI: 10.1021/acs.jnatprod.4c00118
Longcheng Guo, Oscar P. Kuipers and Jaap Broos*,
Antimicrobial peptides (AMPs) have raised significant interest, forming a potential new class of antibiotics in the fight against multi-drug-resistant bacteria. Various AMPs are ribosomally synthesized and post-translationally modified peptides (RiPPs). One post-translational modification found in AMPs is the halogenation of Trp residues. This modification has, for example, been shown to be critical for the activity of the potent AMP NAI-107 from Actinoallomurus. Due to the importance of organohalogens, establishing methods for facile and selective halogen atom installation into AMPs is highly desirable. In this study, we introduce an expression system utilizing the food-grade strain Lactococcus lactis, facilitating the efficient incorporation of bromo-Trp (BrTrp) into (modified) peptides, exemplified by the lantibiotic nisin with a single Trp residue or analogue incorporated at position 1. This provides an alternative to the challenges posed by halogenase enzymes, such as poor substrate selectivity. Our method yields expression levels comparable to that of wild-type nisin, while BrTrp incorporation does not interfere with the post-translational modifications of nisin (dehydration and cyclization). One brominated nisin variant exhibits a 2-fold improvement in antimicrobial activity against two tested pathogens, including a WHO priority pathogen, while maintaining the same lipid II binding and bactericidal activity as wild-type nisin. The work presented here demonstrates the potential of this methodology for peptide halogenation, offering a new avenue for the development of diverse antimicrobial products labeled with BrTrp.
{"title":"Facile Halogenation of Antimicrobial Peptides As Demonstrated by Producing Bromotryptophan-Labeled Nisin Variants with Enhanced Antimicrobial Activity","authors":"Longcheng Guo, Oscar P. Kuipers and Jaap Broos*, ","doi":"10.1021/acs.jnatprod.4c00118","DOIUrl":"10.1021/acs.jnatprod.4c00118","url":null,"abstract":"<p >Antimicrobial peptides (AMPs) have raised significant interest, forming a potential new class of antibiotics in the fight against multi-drug-resistant bacteria. Various AMPs are ribosomally synthesized and post-translationally modified peptides (RiPPs). One post-translational modification found in AMPs is the halogenation of Trp residues. This modification has, for example, been shown to be critical for the activity of the potent AMP NAI-107 from <i>Actinoallomurus</i>. Due to the importance of organohalogens, establishing methods for facile and selective halogen atom installation into AMPs is highly desirable. In this study, we introduce an expression system utilizing the food-grade strain <i>Lactococcus lactis</i>, facilitating the efficient incorporation of bromo-Trp (BrTrp) into (modified) peptides, exemplified by the lantibiotic nisin with a single Trp residue or analogue incorporated at position 1. This provides an alternative to the challenges posed by halogenase enzymes, such as poor substrate selectivity. Our method yields expression levels comparable to that of wild-type nisin, while BrTrp incorporation does not interfere with the post-translational modifications of nisin (dehydration and cyclization). One brominated nisin variant exhibits a 2-fold improvement in antimicrobial activity against two tested pathogens, including a WHO priority pathogen, while maintaining the same lipid II binding and bactericidal activity as wild-type nisin. The work presented here demonstrates the potential of this methodology for peptide halogenation, offering a new avenue for the development of diverse antimicrobial products labeled with BrTrp.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jnatprod.4c00118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}