TY - JOUR
T1 - Identification and heterologous expression of the globomycin biosynthetic gene cluster
AU - Oves-Costales, Daniel
AU - Gren, Tetiana
AU - Sterndorff, Eva Baggesgaard
AU - Martín, Jesús
AU - Ortiz-López, Francisco Javier
AU - Jørgensen, Tue S.
AU - Jiang, Xinglin
AU - Román-Hurtado, Fernando
AU - Reyes, Fernando
AU - Genilloud, Olga
AU - Weber, Tilmann
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - CRISPR-cBEST
KW - Cyclic lipodepsipeptide
KW - Genome mining
KW - Globomycin
KW - Heterologous expression
KW - Signal peptidase II
U2 - 10.1016/j.synbio.2023.02.001
DO - 10.1016/j.synbio.2023.02.001
M3 - Journal article
C2 - 36844473
AN - SCOPUS:85147720163
SN - 2405-805x
VL - 8
SP - 206
EP - 212
JO - Synthetic and Systems Biotechnology
JF - Synthetic and Systems Biotechnology
IS - 2
ER -