GPAHex-A synthetic biology platform for Type IV–V glycopeptide antibiotic production and discovery

• Published in: Nature communications Vol. 11; no. 1; p. 5232
• Main Authors: Xu, Min, Wang, Wenliang, Waglechner, Nicholas, Culp, Elizabeth J., Guitor, Allison K., Wright, Gerard D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-10-2020; Nature Portfolio
• Subjects: 13/44; 14/63; 140/131; 140/58; 38/22; 38/23; 38/77; 38/88; 38/90; 42/41; 45/22; 45/23; 45/29; 631/1647/338/22/1290; 631/326/22/1290; 631/61/318; 631/92/349/977; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19138-5

Glycopeptide antibiotics (GPAs) are essential for the treatment of severe infectious diseases caused by Gram-positive bacteria. The emergence and spread of GPA resistance have propelled the search for more effective GPAs. Given their structural complexity, genetic intractability, and low titer, expansion of GPA chemical diversity using synthetic or medicinal chemistry remains challenging. Here we describe a synthetic biology platform, GPAHex (GPA Heterologous expression), which exploits the genes required for the specialized GPA building blocks, regulation, antibiotic transport, and resistance for the heterologous production of GPAs. Application of the GPAHex platform results in: (1) a 19-fold increase of corbomycin titer compared to the parental strain, (2) the discovery of a teicoplanin-class GPA from an
Amycolatopsis
isolate, and (3) the overproduction and characterization of a cryptic nonapeptide GPA. GPAHex provides a platform for GPA production and mining of uncharacterized GPAs and provides a blueprint for chassis design for other natural product classes.
Expansion of the chemical diversity of glycopeptide antibiotics (GPAs) to deal with the emergence and spread of GPA resistance is challenging. Here, the authors report a GPA synthetic biology platform in
Streptomyces coelicolor
for Type IV–V glycopeptide antibiotic production and discovery.