Chemical synthesis and biosynthesis of darobactin

Antibiotic resistance is a huge public health security crisis around the world. Darobactin is a ribosomally produced and post-translationally modified heptapeptide antibiotic with a unique bicyclic structure. This compound is highly effective against a variety of Gram-negative pathogens by targeting the outer membrane protein BamA. The biosynthetic pathway of darobactin involves a highly versatile radical S-adenosylmethionine (SAM) enzyme DarE, which is responsible for the formation of the unique indole-based bicyclic cyclophane structure. Recently, total synthesis of darobactin was achieved independently by different research groups, utilizing Larock heteroannulation as a key step to construct the bicyclic structure. This paper reviews the recent studies in the chemistry and biology of darobactin, including biosynthetic pathway, chemical synthesis, antibacterial mode of action, and bioengineering studies.