Nargenicin
(Synonyms: 阿根诺卡菌素,Antibiotic 47444) 目录号 : GC40081A macrolide antibiotic
Cas No.:70695-02-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Nargenicin is a macrolide antibiotic that selectively inhibits the growth of S. aureus, methicilin resistant S. aureus (MRSA), and M. luteus (MICs = 0.6, 0.3, and 2.5 μg/ml, respectively) over a panel of 11 Gram-positive and Gram-negative bacteria (MICs = >80 μg/ml). [1] It dose-dependently inhibits S. aureus DnaE in the presence of DNase I-activated DNA and E. coli DnaE when used at concentrations of 0.00001-0.1 and 0.01-100 μg/mL, respectively. [2] In murine BV-2 microglial cells, nargenicin (1 μM) inhibits cytokine expression and nitric oxide production induced by LPS.[3] Nargenicin (200 μM), when used in combination with 1,25-dihydroxyvitamin D3 or all-trans retinoic acid , reduces cell proliferation by 37-47% and increases cell differentiation by 82-85% in HL-60 human myeloid leukemia cells.[4] In vivo, nargenicin (50 mg/kg, p.o.) reduces the number of colony-forming units (CFUs) in infected kidneys by 100,000-fold in a murine model of S. aureus infection.[2]
Reference：
[1]. Sohng, J.K., Yamaguchi, T., Seong, C.N., et al. Production, isolation and biological activity of nargenicin from Nocardia sp. CS682. Arch. Pharm. Res. 31(10), 1339-1345 (2008).
[2]. Painter, R.E., Adam, G.C., Arocho, M., et al. Elucidation of DnaE as the antibacterial target of the natural product, nargenicin. Chem. Biol. 22(10), 1362-1373 (2015).
[3]. Yoo, J.C., Cho, H.S., Park, E., et al. Nargenicin attenuates lipopolysaccharide-induced inflammatory responses in BV-2 cells. Neuroreport 20(11), 1007-1012 (2009).
[4]. Kim, S.H., Yoo, J.C., and Kim, T.S. Nargenicin enhances 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced leukemia cell differentiation via PKCβI/MAPK pathways. Biochem. Pharmacol. 77(11), 1694-1701 (2009).
| Cas No. | 70695-02-2 | SDF | |
| 别名 | 阿根诺卡菌素,Antibiotic 47444 | ||
| 化学名 | 1H-pyrrole-2-carboxylic acid, (1E,3R,4S,7S,8aS,10aR,11R,12R,13R,14R,14aS,14bS)-3,4,6,7,8,8a,10a,11,12,13,14,14a-dodecahydro-14-hydroxy-4-[(1R)-1-hydroxyethyl]-7-methoxy-1,3,13-trimethyl-6-oxo-11,14b-epoxy-14bH-naphth[2,1-e]oxecin-12-yl ester | ||
| 分子式 | C28H37NO8 | 分子量 | 515.6 |
| 溶解度 | DMF: soluble,DMSO: soluble,Ethanol: soluble,Methanol: soluble | 储存条件 | Store at -20°C,protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9395 mL | 9.6974 mL | 19.3949 mL |
| 5 mM | 0.3879 mL | 1.9395 mL | 3.879 mL |
| 10 mM | 0.1939 mL | 0.9697 mL | 1.9395 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The Nargenicin Family of Oxa-Bridged Macrolide Antibiotics
Chemistry 2020 Mar 2;26(13):2780-2792.PMID:31667915DOI:10.1002/chem.201904053.
The Nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad-spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow-spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for Nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure-activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.
DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication in Mycobacterium tuberculosis
ACS Infect Dis 2022 Mar 11;8(3):612-625.PMID:35143160DOI:10.1021/acsinfecdis.1c00643.
Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of Nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of Nargenicin to Mtb DnaE1 requires the DNA substrate such that Nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of Nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on Mtb DnaE1.
Nargenicin A1 attenuates lipopolysaccharide-induced inflammatory and oxidative response by blocking the NF-κB signaling pathway
EXCLI J 2021 May 28;20:968-982.PMID:34267609DOI:10.17179/excli2021-3506.
Inflammation caused by the excessive production of pro-inflammatory mediators and cytokines in abnormally activated macrophages promotes the initiation and progression of many diseases along with oxidative stress. Previous studies have suggested that Nargenicin A1, an antibacterial macrolide isolated from Nocardia sp. may be a potential treatment for inflammatory responses and oxidative stress, but the detailed mechanisms are still not well studied. In this study, we investigated the inhibitory effect of Nargenicin A1 on inflammatory and oxidative stress in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and zebrafish (Danio rerio) models. Our results indicated that Nargenicin A1 treatment significantly inhibited LPS-induced release of pro-inflammatory mediators including nitric oxide (NO) and prostaglandin E2, which was associated with decreased inducible NO synthase and cyclooxygenase-2 expression. In addition, Nargenicin A1 attenuated the LPS-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1, reducing their extracellular secretion. Nargenicin A1 also suppressed LPS-induced generation of reactive oxygen species. Moreover, Nargenicin A1 abolished the LPS-mediated nuclear translocation of nuclear factor-kappa B (NF-κB) and the degradation of inhibitor IκB-α, indicating that Nargenicin A1 exhibited anti-inflammatory effects by inhibiting the NF-κB signaling pathway. Furthermore, Nargenicin A1 showed strong protective effects against NO and ROS production in LPS-injected zebrafish larvae. In conclusion, our findings suggest that Nargenicin A1 ameliorates LPS-induced anti-inflammatory and antioxidant effects by downregulating the NF-κB signaling pathway, and that Nargenicin A1 can be a potential functional agent to prevent inflammatory- and oxidative-mediated damage.
Biosynthesis and Ether-Bridge Formation in Nargenicin Macrolides
Angew Chem Int Ed Engl 2019 Mar 18;58(12):3996-4001.PMID:30677204DOI:10.1002/anie.201900290.
The Nargenicin family of antibiotics are macrolides containing a rare ether-bridged cis-decalin motif. Several of these compounds are highly active against multi-drug resistant organisms. Despite the identification of the first members of this family almost 40 years ago, the genetic basis for the production of these molecules and the enzyme responsible for formation of the oxa bridge, remain unknown. Here, the 85 kb Nargenicin biosynthetic gene cluster was identified from a human pathogenic Nocardia arthritidis isolate and this locus is solely responsible for Nargenicin production. Further investigation of this locus revealed a putative iron-α-ketoglutarate-dependent dioxygenase, which was found to be responsible for the formation of the ether bridge from the newly identified deoxygenated precursor, 8,13-deoxynargenicin. Uncovering the Nargenicin biosynthetic locus provides a molecular basis for the rational bioengineering of these interesting antibiotic macrolides.
Enhanced production of Nargenicin A(1) and generation of novel glycosylated derivatives
Appl Biochem Biotechnol 2015 Mar;175(6):2934-49.PMID:25577346DOI:10.1007/s12010-014-1472-3.
Nargenicin A1, an antibacterial polyketide macrolide produced by Nocardia sp. CS682, was enhanced by increasing the pool of precursors using different sources. Furthermore, by using engineered strain Nocardia sp. ACC18 and supplementation of glucose and glycerol, enhancement was ~7.1 fold in comparison to Nocardia sp. CS682 without supplementation of any precursors. The overproduced compound was validated by mass spectrometry and nuclear magnetic resonance analyses. The novel glycosylated derivatives of purified Nargenicin A1 were generated by efficient one-pot reaction systems in which the syntheses of uridine diphosphate (UDP)-α-D-glucose and UDP-α-D-2-deoxyglucose were modified and combined with glycosyltransferase (GT) from Bacillus licheniformis. Nargenicin A1 11-O-β- D-glucopyranoside, Nargenicin A1 18-O-β-D-glucopyranoside, Nargenicin A111 18-O-β-D- diglucopyranoside, and Nargenicin 11-O-β-D-2-deoxyglucopyranoside were generated. Nargenicin A1 11-O-β-D-glucopyranoside was structurally elucidated by ultra-high performance liquid chromatography-photodiode array (UPLC-PDA) conjugated with high-resolution quantitative time-of-flight-electrospray ionization mass spectroscopy (HR-QTOF ESI-MS/MS), supported by one- and two-dimensional nuclear magnetic resonance studies, whereas other Nargenicin A1 glycosides were characterized by UPLC-PDA and HR-QTOF ESI-MS/MS analyses. The overall conversion studies indicated that the one-pot synthesis system is a highly efficient strategy for production of glycosylated derivatives of compounds like macrolides as well. Furthermore, assessment of solubility indicated that there was enhanced solubility in the case of glycoside, although a substantial increase in activity was not observed.