Pyridomycin
(Synonyms: 吡啶霉素) 目录号 : GC40825
An antimycobacterial antibiotic
Cas No.:18791-21-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pyridomycin is a structurally unusual antimycobacterial cyclodepsipeptide whose composition includes two rare moieties: 3-(3-pyridyl)-L-alanine and 2-hydroxy-3-methylpent-2-enoic acid. It inhibits NADH-dependent enoyl (Acyl-Carrier-Protein) reductase InhA, preventing mycolic acid synthesis in M. tuberculosis, including isoniazid-resistant strains (MICs = 0.31-0.63 µg/ml).
| Cas No. | 18791-21-4 | SDF | |
| 别名 | 吡啶霉素 | ||
| Canonical SMILES | OC1=C(C(N[C@@H]([C@@H](C)OC(/C(O2)=C(C)/CC)=O)C(N[C@@H](CC3=CC=CN=C3)[C@@H](O)[C@@H](C)C2=O)=O)=O)N=CC=C1 | ||
| 分子式 | C27H32N4O8 | 分子量 | 540.6 |
| 溶解度 | DMF: Soluble,DMSO: Soluble,Ethanol: Soluble,Methanol: Soluble | 储存条件 | Store at -20°C |
| 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 | 1.8498 mL | 9.249 mL | 18.498 mL |
| 5 mM | 0.37 mL | 1.8498 mL | 3.6996 mL |
| 10 mM | 0.185 mL | 0.9249 mL | 1.8498 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。
Characterization of Pyridomycin B Reveals the Formation of Functional Groups in Antimycobacterial Pyridomycin
Appl Environ Microbiol 2022 Mar 22;88(6):e0203521.PMID:35108072DOI:10.1128/AEM.02035-21.
Pyridomycin, a cyclodepsipeptide with potent antimycobacterial activity, specifically inhibits the InhA enoyl reductase of Mycobacterium tuberculosis. Structure-activity relationship studies indicated that the enolic acid moiety in the Pyridomycin core system is an important pharmacophoric group, and the natural configuration of the C-10 hydroxyl contributes to the bioactivity of Pyridomycin. The ring structure of Pyridomycin was generated by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) hybrid system (PyrE-PyrF-PyrG). Bioinformatics analysis reveals that short-chain dehydrogenase/reductase (SDR) family protein Pyr2 functions as a 3-oxoacyl acyl carrier protein (ACP) reductase in the Pyridomycin pathway. Inactivation of pyr2 resulted in accumulation of Pyridomycin B, a new Pyridomycin analogue featured with enol moiety in pyridyl alanine moiety and a saturated 3-methylvaleric acid group. The elucidated structure of Pyridomycin B suggests that rather than functioning as a post-tailoring enzyme, Pyr2 catalyzes ketoreduction to form the C-10 hydroxyl group in pyridyl alanine moiety and the double bond formation of the enolic acid moiety derived from isoleucine when the intermediate assembled by PKS-NRPS machinery is still tethered to the last NRPS module in a special energy-saving manner. Ser-His-Lys residues constitute the active site of Pyr2, which is different from the typically conserved Tyr-based catalytic triad in the majority of SDRs. Site-directed mutation identified that His154 in the active site is a critical residue for Pyridomycin B production. These findings will improve our understanding of Pyridomycin biosynthetic logic, identify the missing link for the double bound formation of enol ester in Pyridomycin, and enable the creation of chemical diversity of Pyridomycin derivatives. IMPORTANCE Tuberculosis (TB) is one of the world's leading causes of death by infection. Recently, Pyridomycin, the antituberculous natural product from Streptomyces has garnered considerable attention for being determined as a target inhibitor of InhA enoyl reductase of Mycobacterium tuberculosis. In this study, we report a new Pyridomycin analogue from mutant HTT12, demonstrate the essential role of a previously ignored gene pyr2 in Pyridomycin biosynthetic pathway, and imply that Pyr2 functions as a trans ketoreductase (KR) contributing to the formation of functional groups of Pyridomycin utilizing a distinct catalytic mechanism. As enol moiety are important for pharmaceutical activities of Pyridomycin, our work would expand our understanding of the mechanism of SDR family proteins and set the stage for future bioengineering of new Pyridomycin derivatives.
Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA
Nat Chem Biol 2014 Feb;10(2):96-8.PMID:24292073DOI:10.1038/nchembio.1405.
Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of Pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new Pyridomycin derivatives.
Towards a new tuberculosis drug: Pyridomycin - nature's isoniazid
EMBO Mol Med 2012 Oct;4(10):1032-42.PMID:22987724DOI:10.1002/emmm.201201689.
Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe Pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that Pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that Pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to Pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.
Synthesis and Structure-Activity Relationship Studies of C2-Modified Analogs of the Antimycobacterial Natural Product Pyridomycin
J Med Chem 2020 Feb 13;63(3):1105-1131.PMID:31904960DOI:10.1021/acs.jmedchem.9b01457.
A series of derivatives of the antimycobacterial natural product Pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of sufficient size generally provide for potent anti-Mtb activity of these dihydropyridomycins (minimum inhibitory concentration (MIC) values around 2.5 μM), with several analogs thus approaching the activity of natural Pyridomycin. Surprisingly, some of these compounds, in contrast to Pyridomycin, are insensitive to overexpression of InhA in Mycobacterium tuberculosis (Mtb). This indicates that their anti-Mtb activity does not critically depend on the inhibition of InhA and that their overall mode of action may differ from that of the original natural product lead.
Identification and characterization of the Pyridomycin biosynthetic gene cluster of Streptomyces pyridomyceticus NRRL B-2517
J Biol Chem 2011 Jun 10;286(23):20648-57.PMID:21454714DOI:10.1074/jbc.M110.180000.
Pyridomycin is a structurally unique antimycobacterial cyclodepsipeptide containing rare 3-(3-pyridyl)-l-alanine and 2-hydroxy-3-methylpent-2-enoic acid moieties. The biosynthetic gene cluster for Pyridomycin has been cloned and identified from Streptomyces pyridomyceticus NRRL B-2517. Sequence analysis of a 42.5-kb DNA region revealed 26 putative open reading frames, including two nonribosomal peptide synthetase (NRPS) genes and a polyketide synthase gene. A special feature is the presence of a polyketide synthase-type ketoreductase domain embedded in an NRPS. Furthermore, we showed that PyrA functioned as an NRPS adenylation domain that activates 3-hydroxypicolinic acid and transfers it to a discrete peptidyl carrier protein, PyrU, which functions as a loading module that initiates Pyridomycin biosynthesis in vivo and in vitro. PyrA could also activate other aromatic acids, generating three Pyridomycin analogues in vivo.