Biosynthesis and Ether-Bridge Formation in Nargenicin Macrolides

Area of Science:

• Microbiology
• Molecular Biology
• Natural Product Chemistry

Background:

• Nargenicin antibiotics are macrolides with a rare cis-decalin motif, showing high activity against multi-drug resistant organisms.
• The genetic basis for nargenicin production and the enzyme forming its characteristic oxa bridge have remained elusive for nearly 40 years.

Purpose of the Study:

• To identify the biosynthetic gene cluster responsible for nargenicin production.
• To elucidate the enzyme and mechanism involved in forming the unique ether bridge in nargenicin antibiotics.

Main Methods:

• Identification and characterization of the 85 kb nargenicin biosynthetic gene cluster from Nocardia arthritidis.
• Biochemical analysis to determine the function of a putative iron-α-ketoglutarate-dependent dioxygenase in forming the ether bridge.

Main Results:

• The complete 85 kb nargenicin biosynthetic gene cluster was identified and confirmed to be solely responsible for nargenicin production.
• A specific iron-α-ketoglutarate-dependent dioxygenase was identified as the enzyme catalyzing ether bridge formation from an 8,13-deoxynargenicin precursor.

Conclusions:

• The genetic basis for nargenicin biosynthesis has been uncovered.
• The enzyme responsible for the crucial ether bridge formation has been identified, providing a target for future research.
• This work lays the foundation for the rational bioengineering of nargenicin antibiotics for therapeutic applications.