Chloroeremomycin
[CAS# 118395-73-6]

Identification

• Classification: API >> Antibiotics
• Name: Chloroeremomycin
• Synonyms: Chloroorienticin A; A 82846B; A83846b; (1S,2R,18R,19R,22S,25R,28R,40S)-22-(2-Amino-2-oxoethyl)-48-{[2-O-(3-amino-2,3,6-trideoxy-3-methyl-a-L-arabino-hexopyranosyl)-�-D-glucopyranosyl]oxy}-2-[(3-amino-2,3,6-trideoxy-3-methyl-a-L- arabino-hexopyranosyl)oxy]-5,15-dichloro-18,32,35,37-tetrahydroxy-19-[(N-methyl-D-leucyl)amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2~3,6~.2~14,17~.1~8,12~.1~29 ,33~.0~10,25~.0~34,39~]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34,36,38,46,49-pentadecaene-40-carboxylic acid
• Molecular Formula: C₇₃H₈₈Cl₂N₁₀O₂₆
• Molecular Weight: 1592.44
• CAS Registry Number: 118395-73-6
• SMILES: CN[C@H](CC(C)C)C(=O)N[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H]2C(=O)N[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)O)c4cc(O)cc(O)c4-c4cc3ccc4O)[C@H](O[C@H]3C[C@](C)(N)[C@@H](O)[C@H](C)O3)c3ccc(c(Cl)c3)Oc3cc2cc(c3O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O[C@H]2C[C@](C)(N)[C@@H](O)[C@H](C)O2)Oc2ccc(cc2Cl)[C@H]1O

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Index of refraction: 1.719 (Calc.)^*

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

Discovory and Applicatios

Chloroeremomycin is a glycopeptide antibiotic isolated from the bacterium Amycolatopsis orientalis, discovered by Eli Lilly in the 1980s during efforts to identify novel antibiotics to combat bacterial resistance. Belonging to the vancomycin family, it features a complex structure with a heptapeptide core, glycosylations, and chlorinated residues, making it a significant subject in antibiotic research. Its discovery was driven by the urgent need to address the growing threat of vancomycin-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The identification of chloroeremomycin marked a critical advancement in glycopeptide antibiotics, as its structural differences from vancomycin offered improved activity against resistant strains, paving the way for the development of semi-synthetic derivatives like oritavancin.

The chemical structure of chloroeremomycin consists of a non-ribosomal heptapeptide backbone with seven amino acids: N-methyl-L-leucine, L-tyrosine, D-asparagine, D-4-hydroxyphenylglycine, L-4-hydroxyphenylglycine, D-tyrosine, and D-3,5-dihydroxyphenylglycine. The peptide is modified with oxidative cross-links between aromatic side chains, chlorination of the two tyrosine residues, and glycosylation at two sites. The fourth amino acid bears a disaccharide of D-glucose linked to L-4-epi-vancosamine, while the sixth amino acid carries a monosaccharide of L-4-epi-vancosamine linked to D-beta-hydroxytyrosine. These modifications enhance its binding affinity to bacterial cell wall precursors, distinguishing it from vancomycin, which lacks the additional epivancosamine at the sixth position. The molecular formula is C₇₃H₈₈Cl₂N₁₀O₂₆, reflecting its structural complexity.

The biosynthesis of chloroeremomycin involves a non-ribosomal peptide synthetase encoded by three genes: CepA, CepB, and CepC. CepA links the first three amino acids, CepB adds the next three, and CepC incorporates the final amino acid and releases the peptide. Each amino acid is processed by modules with adenylation, peptide carrier protein, and condensation domains, with epimerization domains adjusting stereochemistry in specific modules. Tailoring enzymes perform chlorination, glycosylation, methylation, oxidative cross-linking, and hydroxylation. Glycosylation is catalyzed by glycosyltransferases GtfA, GtfB, and GtfC, attaching glucose and epivancosamine units. The deoxysugar L-4-epi-vancosamine is synthesized from TDP-4-keto-6-deoxy-D-glucose through a series of enzymatic steps, including deoxygenation, amination, methylation, epimerization, and ketoreduction. The sequencing of the chloroeremomycin gene cluster in 1998 provided a foundation for understanding its biosynthetic pathway and exploring combinatorial biosynthesis.

Chloroeremomycin’s primary application is as a precursor for oritavancin, a semi-synthetic lipoglycopeptide developed by Eli Lilly and later approved by the FDA in 2014 for treating acute bacterial skin and skin structure infections. Oritavancin is derived by adding a 4'-chlorobiphenylmethyl group and an extra epivancosamine to chloroeremomycin, enhancing its activity against MRSA, VRE, and vancomycin-intermediate Staphylococcus aureus. Unlike vancomycin, oritavancin’s long half-life allows single-dose administration, improving patient compliance. Chloroeremomycin itself has not been used clinically due to its complex structure and the superior properties of oritavancin but remains crucial in research. It serves as a model for studying glycopeptide biosynthesis, particularly the roles of non-ribosomal peptide synthetases, glycosyltransferases, and tailoring enzymes. Its mechanism of action, like vancomycin, involves binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors, inhibiting cell wall synthesis in Gram-positive bacteria. The additional epivancosamine enhances its binding to cell wall components, improving efficacy against resistant strains.

In research, chloroeremomycin has been instrumental in advancing antibiotic development. Its gene cluster has been used to investigate enzymatic pathways and engineer novel glycopeptides through combinatorial biosynthesis. The compound’s structural complexity and biosynthetic insights have informed strategies to combat antibiotic resistance, a pressing global health issue. Its role in yielding oritavancin underscores its impact on modern therapeutics, addressing challenges posed by multidrug-resistant bacteria.

References

1988. New glycopeptide antibiotics: II. The isolation and structures of chloroorienticins. The Journal of Antibiotics, 41(10).
DOI: 10.7164/antibiotics.41.1506

1989. The structural relationships of A82846B and its hydrolysis products with chloroorienticins A, B and C. The Journal of Antibiotics, 42(9).
DOI: 10.7164/antibiotics.42.1438