Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of streptomyces fungicidicus

Xihou Yin, Ying Chen, Ling Zhang, Yang Wang, Mark Zabriskie

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Enduracidins (1, 2) and ramoplanin (3) are structurally and functionally closely related lipodepsipeptide antibiotics. They are active against multi-drug-resistant Gram-positive pathogens, including MRSA. Each peptide contains one chlorinated non-proteinogenic amino acid residue, Cl 2-Hpg or Cl-Hpg. To investigate the timing of halogenation and the importance of chlorination on bioactivity and bioavailability of enduracidin, and to probe the substrate specificity and portability of the ramoplanin halogenase, we constructed the mutant strain SfΔ30 in which the enduracidin halogenase gene orf30 had been deleted and complemented it with the ramoplanin counterpart orf20. We also expressed orf20 in the enduracidin wild-type producer. Metabolite analysis revealed SfΔ30 produced the novel analogues dideschloroenduracidins A (4) and B (5), while the recombinant strains Sf?30R20 and SfR20 produced monodeschloroenduracidins A (6) and B (7) and a trichlorinated enduracidin (8), respectively. In addition, orf30 self-complementation yielded the strain Sf?30E30, which is capable of producing six peptides including 6 and 7. MS/MS analysis positioned the single chlorine atom in 6 at Hpg13 and localized the third chlorine atom in 8 to Hpg11. Biological evaluation of these enduracidin analogues indicated that all retained activity against Staphylococcus aureus. Our findings lay the foundation for further utilization of enduracidin and ramoplanin halogenases in combinatorial biosynthesis.

Original languageEnglish (US)
Pages (from-to)583-589
Number of pages7
JournalJournal of Natural Products
Volume73
Issue number4
DOIs
StatePublished - Apr 23 2010
Externally publishedYes

Fingerprint

ramoplanin
Halogenation
Streptomyces
Chlorine
Atoms
Peptides
Chlorination
Biosynthesis
Pathogens
Methicillin-Resistant Staphylococcus aureus
Metabolites
Substrate Specificity
Bioactivity
Biological Availability
Staphylococcus aureus
Genes
Anti-Bacterial Agents
Amino Acids
Substrates
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Complementary and alternative medicine
  • Molecular Medicine
  • Organic Chemistry
  • Analytical Chemistry
  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

Cite this

Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of streptomyces fungicidicus. / Yin, Xihou; Chen, Ying; Zhang, Ling; Wang, Yang; Zabriskie, Mark.

In: Journal of Natural Products, Vol. 73, No. 4, 23.04.2010, p. 583-589.

Research output: Contribution to journalArticle

@article{bac45142317e4b0d9c9bdeb613719059,
title = "Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of streptomyces fungicidicus",
abstract = "Enduracidins (1, 2) and ramoplanin (3) are structurally and functionally closely related lipodepsipeptide antibiotics. They are active against multi-drug-resistant Gram-positive pathogens, including MRSA. Each peptide contains one chlorinated non-proteinogenic amino acid residue, Cl 2-Hpg or Cl-Hpg. To investigate the timing of halogenation and the importance of chlorination on bioactivity and bioavailability of enduracidin, and to probe the substrate specificity and portability of the ramoplanin halogenase, we constructed the mutant strain SfΔ30 in which the enduracidin halogenase gene orf30 had been deleted and complemented it with the ramoplanin counterpart orf20. We also expressed orf20 in the enduracidin wild-type producer. Metabolite analysis revealed SfΔ30 produced the novel analogues dideschloroenduracidins A (4) and B (5), while the recombinant strains Sf?30R20 and SfR20 produced monodeschloroenduracidins A (6) and B (7) and a trichlorinated enduracidin (8), respectively. In addition, orf30 self-complementation yielded the strain Sf?30E30, which is capable of producing six peptides including 6 and 7. MS/MS analysis positioned the single chlorine atom in 6 at Hpg13 and localized the third chlorine atom in 8 to Hpg11. Biological evaluation of these enduracidin analogues indicated that all retained activity against Staphylococcus aureus. Our findings lay the foundation for further utilization of enduracidin and ramoplanin halogenases in combinatorial biosynthesis.",
author = "Xihou Yin and Ying Chen and Ling Zhang and Yang Wang and Mark Zabriskie",
year = "2010",
month = "4",
day = "23",
doi = "10.1021/np900710q",
language = "English (US)",
volume = "73",
pages = "583--589",
journal = "Journal of Natural Products",
issn = "0163-3864",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of streptomyces fungicidicus

AU - Yin, Xihou

AU - Chen, Ying

AU - Zhang, Ling

AU - Wang, Yang

AU - Zabriskie, Mark

PY - 2010/4/23

Y1 - 2010/4/23

N2 - Enduracidins (1, 2) and ramoplanin (3) are structurally and functionally closely related lipodepsipeptide antibiotics. They are active against multi-drug-resistant Gram-positive pathogens, including MRSA. Each peptide contains one chlorinated non-proteinogenic amino acid residue, Cl 2-Hpg or Cl-Hpg. To investigate the timing of halogenation and the importance of chlorination on bioactivity and bioavailability of enduracidin, and to probe the substrate specificity and portability of the ramoplanin halogenase, we constructed the mutant strain SfΔ30 in which the enduracidin halogenase gene orf30 had been deleted and complemented it with the ramoplanin counterpart orf20. We also expressed orf20 in the enduracidin wild-type producer. Metabolite analysis revealed SfΔ30 produced the novel analogues dideschloroenduracidins A (4) and B (5), while the recombinant strains Sf?30R20 and SfR20 produced monodeschloroenduracidins A (6) and B (7) and a trichlorinated enduracidin (8), respectively. In addition, orf30 self-complementation yielded the strain Sf?30E30, which is capable of producing six peptides including 6 and 7. MS/MS analysis positioned the single chlorine atom in 6 at Hpg13 and localized the third chlorine atom in 8 to Hpg11. Biological evaluation of these enduracidin analogues indicated that all retained activity against Staphylococcus aureus. Our findings lay the foundation for further utilization of enduracidin and ramoplanin halogenases in combinatorial biosynthesis.

AB - Enduracidins (1, 2) and ramoplanin (3) are structurally and functionally closely related lipodepsipeptide antibiotics. They are active against multi-drug-resistant Gram-positive pathogens, including MRSA. Each peptide contains one chlorinated non-proteinogenic amino acid residue, Cl 2-Hpg or Cl-Hpg. To investigate the timing of halogenation and the importance of chlorination on bioactivity and bioavailability of enduracidin, and to probe the substrate specificity and portability of the ramoplanin halogenase, we constructed the mutant strain SfΔ30 in which the enduracidin halogenase gene orf30 had been deleted and complemented it with the ramoplanin counterpart orf20. We also expressed orf20 in the enduracidin wild-type producer. Metabolite analysis revealed SfΔ30 produced the novel analogues dideschloroenduracidins A (4) and B (5), while the recombinant strains Sf?30R20 and SfR20 produced monodeschloroenduracidins A (6) and B (7) and a trichlorinated enduracidin (8), respectively. In addition, orf30 self-complementation yielded the strain Sf?30E30, which is capable of producing six peptides including 6 and 7. MS/MS analysis positioned the single chlorine atom in 6 at Hpg13 and localized the third chlorine atom in 8 to Hpg11. Biological evaluation of these enduracidin analogues indicated that all retained activity against Staphylococcus aureus. Our findings lay the foundation for further utilization of enduracidin and ramoplanin halogenases in combinatorial biosynthesis.

UR - http://www.scopus.com/inward/record.url?scp=77951560592&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951560592&partnerID=8YFLogxK

U2 - 10.1021/np900710q

DO - 10.1021/np900710q

M3 - Article

C2 - 20353165

AN - SCOPUS:77951560592

VL - 73

SP - 583

EP - 589

JO - Journal of Natural Products

JF - Journal of Natural Products

SN - 0163-3864

IS - 4

ER -