Echinocandin B
[CAS# 54651-05-7]

Identification

• Classification: API >> Antibiotics
• Name: Echinocandin B
• Synonyms: 1H-Dipyrrolo[2,1-c:2',1'-l][1,4,7,10,13,16]hexaazacycloheneicosine, cyclic peptide deriv.; A 30912 factor A; Antibiotic A 22082; [1(Z,Z),6(2alpha,3beta,4beta)]-(4R,5R)-4,5-Dihydroxy-N2-(1-oxo-9,12-octadecadienyl)-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy-4-(4-hydroxyphenyl)-L-threonyl-L-threonyl-3-hydroxy-4-methyl-L-proline cyclic (6?1)-peptide
• Molecular Formula: C₅₂H₈₁N₇O₁₆
• Molecular Weight: 1060.24
• CAS Registry Number: 54651-05-7
• EC Number: 658-057-8
• SMILES: CCCCC/C=C\C/C=C\CCCCCCCC(=O)N[C@H]1C[C@H]([C@H](NC(=O)[C@@H]2[C@H]([C@H](CN2C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@@H](NC1=O)[C@@H](C)O)O)[C@@H]([C@H](C4=CC=C(C=C4)O)O)O)[C@@H](C)O)C)O)O)O

Properties

• Solubility: Insoluble (8.9E^-4 g/L) (25 ºC), Calc.^*
• Density: 1.37±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Boiling point: 1384.0±65.0 ºC 760 mmHg (Calc.)^*
• Flash point: 790.8±34.3 ºC (Calc.)^*
• Index of refraction: 1.627 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08 Warning
• Hazard Statements: H302-H319-H361
• Precautionary Statements: P203-P264-P264+P265-P270-P280-P301+P317-P305+P351+P338-P318-P330-P337+P317-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2	H319

Discovory and Applicatios

Echinocandin B, with the molecular formula C₅₂H₈₁N₇O₁₆ and CAS number 54651-05-7, is a naturally occurring lipopeptide antifungal compound produced by the fungus Aspergillus nidulans var. echinulatus. It belongs to the echinocandin class of antifungals, known for their activity against fungal cell wall synthesis. Its discovery and applications are well-documented in the literature, stemming from the exploration of microbial metabolites with antifungal properties.

The discovery of echinocandin B occurred in the early 1970s by researchers at Sandoz (now Novartis) in Switzerland during a screening program for novel antifungal agents. Isolated from the fermentation broth of Aspergillus nidulans var. echinulatus, it was identified alongside other echinocandins (A, C, and D) as a cyclic hexapeptide with a lipophilic side chain. The compound’s potent activity against Candida species, particularly Candida albicans, addressed the need for new antifungals amid rising resistance to polyenes like amphotericin B and azoles. Echinocandin B’s discovery built on advances in microbial fermentation and natural product chemistry, with its structure elucidated in the 1970s using NMR and mass spectrometry. Its cyclic peptide core and linoleoyl side chain were found to be critical for its antifungal mechanism, paving the way for semi-synthetic derivatives like anidulafungin, approved in 2006 for treating invasive fungal infections.

Synthetically, echinocandin B is produced via fermentation of Aspergillus nidulans var. echinulatus in a nutrient-rich medium containing glucose, amino acids, and inorganic salts. The fungus is cultured aerobically, and the lipopeptide is extracted from the mycelial biomass using organic solvents like methanol or ethyl acetate, followed by purification through silica gel chromatography or reverse-phase HPLC. The chemical structure consists of a cyclic hexapeptide composed of 4-hydroxyproline, 4,5-dihydroxyornithine, 3,4-dihydroxyhomotyrosine, 3-hydroxy-4-methylproline, threonine, and 3-hydroxyproline, with a linoleoyl side chain attached to the ornithine residue. Total chemical synthesis of echinocandin B is feasible but complex, involving solid-phase peptide synthesis and cyclization, followed by acylation with linoleic acid. However, fermentation remains the primary production method due to its efficiency and scalability. These processes rely on established protocols in fungal biotechnology and peptide purification.

The primary application of echinocandin B is as a lead compound and intermediate in antifungal drug development. It is not used clinically due to its hemolytic activity and poor solubility but serves as a precursor for semi-synthetic echinocandins. Its mechanism of action involves non-competitive inhibition of 1,3-beta-D-glucan synthase, an enzyme essential for fungal cell wall synthesis, leading to osmotic instability and fungal cell death. This mechanism is effective against Candida and Aspergillus species but not Cryptococcus, due to differences in cell wall composition. Echinocandin B’s linoleoyl side chain enhances membrane interaction, but its hemolytic potential led to the development of anidulafungin, which replaces the linoleoyl group with a terphenylcarboxylic acid, improving safety and efficacy. Anidulafungin is used for candidemia, esophageal candidiasis, and invasive aspergillosis.

In academic research, echinocandin B is studied for its biosynthesis, involving non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS), with the gene cluster identified in the 2000s. Its structure-activity relationships have informed the design of echinocandin analogs, focusing on optimizing the lipophilic side chain and peptide core. The compound is also used to investigate fungal cell wall dynamics and resistance mechanisms, particularly mutations in the FKS1 gene encoding glucan synthase. Its significance lies in its role as a foundational echinocandin, driving the development of safer, clinically effective antifungals and advancing fungal biotechnology and medicinal chemistry.

References

1974. Metabolites of microorganisms. 143. Echinocandin B, a novel polypeptide-antibiotic from Aspergillus nidulans var. echinulatus: isolation and structural components. Helvetica Chimica Acta, 57(8).
DOI: 10.1002/hlca.19740570818

2012. Identification and Characterization of the Echinocandin B Biosynthetic Gene Cluster from Emericella rugulosa NRRL 11440. Journal of the American Chemical Society, 134(39).
DOI: 10.1021/ja307220z

2018. Cryptic Production of trans-3-Hydroxyproline in Echinocandin B Biosynthesis. Applied and Environmental Microbiology, 84(7).
DOI: 10.1128/aem.02370-17