B. subtilis contains three proteins with actin-like function, MreB, Mbl and MreBH, which help to maintain the bacteria’s rod like structure. Deletion of mbl results in a B. subtilis strain which grows very poorly and with a non-rod like shape, but normal growth and shape can be recovered in the presence of Mg2+ (20 mM). We have used B. subtilis Dmbl to screen for new natural products from streptomyces capable of growth rescue, in the absence of added Mg2+, resulting in the discovery of DC616A. Herein we describe the determination of the structure of DC616A by NMR and HRMS, and the absolute stereochemistry by Marfey’s analysis. DC616A is shown to be a polypeptide based siderophore. We have carried out a total synthesis to give DC616A in a 12% overall yield in 12 synthetic steps, based on the longest linear pathway. Synthetic and natural DC616A show identical bioactivity in the growth recovery of B. subtilis Dmbl, validating that the observed bioactivity can be attributed to DC616A. Ongoing work is focussed gaining a greater understanding of the mode-of-action of DC616A.

Discovery, synthesis and biological investigation of the siderophore natural product DC616A

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