Identification and heterologous expression of the globomycin biosynthetic gene cluster

Daniel Oves-Costales*, Tetiana Gren, Eva Baggesgaard Sterndorff, Jesús Martín, Francisco Javier Ortiz-López, Tue S. Jørgensen, Xinglin Jiang, Fernando Román-Hurtado, Fernando Reyes, Olga Genilloud*, Tilmann Weber*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative pathogens. Its mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II (LspA), which is absent in eukaryotes and considered an attractive target for the development of new antibiotics. Despite its interesting biological properties, the gene cluster encoding its biosynthesis has not yet been identified. In this study we employed a genome-mining approach in the globomycin-producing Streptomyces sp. CA-278952 to identify a candidate gene cluster responsible for its biosynthesis. A null mutant was constructed using CRISPR base editing where production was abolished, strongly suggesting its involvement in the biosynthesis. The putative gene cluster was then cloned and heterologously expressed in Streptomyces albus J1074 and Streptomyces coelicolor M1146, therefore unambiguously linking globomycin and its biosynthetic gene cluster. Our work paves the way for the biosynthesis of new globomycin derivatives with improved pharmacological properties.

Original languageEnglish
JournalSynthetic and Systems Biotechnology
Volume8
Issue number2
Pages (from-to)206-212
Number of pages7
ISSN2405-805x
DOIs
Publication statusPublished - 2023

Keywords

  • CRISPR-cBEST
  • Cyclic lipodepsipeptide
  • Genome mining
  • Globomycin
  • Heterologous expression
  • Signal peptidase II

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