Development of a platform for the discovery and practical synthesis of new tetracycline antibiotics

Tetracyclines have proven to be safe and effective antibiotics over decades but to date all approved members of the class have been discovered and manufactured by chemical modification of fermentation products, which greatly limits the number of new structures that can be explored as future medicines. This review summarizes research leading to the development of a platform synthetic technology that enabled the discovery of the clinical candidate eravacycline, as well as other promising new tetracycline antibiotics, and provides the basis for a practical route for their manufacture. The approach argues for a reassessment of other antibiotic classes based on natural products for which practical, fully synthetic routes have not yet been developed, suggesting that these may represent underdeveloped resources with great potential to offer safer and more effective anti-infective agents.