Jadomycins, put a bigger ring in it: isolation of seven- to ten-membered ring analogues

Abstract

We report the production, isolation, and characterization of jadomycins with seven-, nine-, and ten-membered E-rings, all of which are unique natural product ring scaffolds. This significantly expands the scope of a non-enzymatic biosynthetic step in jadomycin biosynthesis in order to produce novel natural products.

Isolation of a post-PKS C–C branching jadomycin from S. venezuelae ISP5230 in the presence of 8-aminooctanoic acid

“…Streptomyces venezuelae ISP5230 VS1099 plates and cultures were grown as previously described, 26 with the exception that 15 mM D-serine was also included in the production media alongside 8-aminooctanoic acid at 60 mM. 28 The resulting natural products were isolated and characterized as described in the supplemental information.…”

“…Streptomyces venezuelae ISP2530 VS1099 demonstrated only limited proliferation and negligible jadomycin production in cultures with 8-aminooctanoic acid (8AA) as the sole nitrogen source, 26 indicating the bacteria was incapable of effectively utilizing the compound as a nutrient source. Further productions were conducted using recently developed methodology, 28 wherein D-serine was included in the production media at 15 mM, a concentration sufficient to support Streptomyces proliferation in the presence of 8AA.…”

“…17,[22][23][24] A series of jadomycins, derived from straight-chain alkyl amino acids (NH 2 (CH 2 ) n COOH, n= 3-5), containing 6-to 9-membered E-rings ( Figure 1) have been isolated and characterized previously. 22,25,26 The jadomycin derived from 7aminoheptanoic acid (7AA) was not cyclized in the E-ring, instead an analogue was isolated with incorporation of the amino acid together with an additional two carbon fragment substituted at the 3a position. 26,27 Attempts to produce jadomycin analogues incorporating 8-aminooctanoic acid (8-D r a f t aminocaprylic acid, 8AA) as the sole nitrogen source in the S. venezuelae cultures were previously unsuccessful, displaying limited cellular proliferation and negligible jadomycin production.…”

“…22,25,26 The jadomycin derived from 7aminoheptanoic acid (7AA) was not cyclized in the E-ring, instead an analogue was isolated with incorporation of the amino acid together with an additional two carbon fragment substituted at the 3a position. 26,27 Attempts to produce jadomycin analogues incorporating 8-aminooctanoic acid (8-D r a f t aminocaprylic acid, 8AA) as the sole nitrogen source in the S. venezuelae cultures were previously unsuccessful, displaying limited cellular proliferation and negligible jadomycin production. 26 Subsequently, a co-amino acid supplementation method was developed for jadomycin productions using amino acids that did not support growth of S. venezuelae.…”

“…26,27 Attempts to produce jadomycin analogues incorporating 8-aminooctanoic acid (8-D r a f t aminocaprylic acid, 8AA) as the sole nitrogen source in the S. venezuelae cultures were previously unsuccessful, displaying limited cellular proliferation and negligible jadomycin production. 26 Subsequently, a co-amino acid supplementation method was developed for jadomycin productions using amino acids that did not support growth of S. venezuelae. 23 The results of these efforts were recently reported showing that supplementation of the culture media with D-serine (DS) could support cell growth and allow each 4-and 3-aminomethylbenzoic acid (4-AMBA, 3-AMBA), which were unable to support cell proliferation, to be incorporated into the jadomycin structure.…”