Background:The emergence of drug-resistant tuberculosis has called for the discovery of new antitubercular drugs. Results: We successfully generated 24-desmethylrifampicin by modifying the rifamycin polyketide backbone. Conclusion: 24-Desmethylrifamycin showed better antibacterial activity than rifampicin against multidrug-resistant strains of Mycobacterium tuberculosis. Significance: The combined genetic-synthetic strategy used in the study has opened up new avenues for generating more rifamycin analogs.

Glycosyltransferases are ubiquitous in nature. They catalyze a glycosidic bond formation between sugar donors and sugar or non-sugar acceptors to produce oligo/polysaccharides, glycoproteins, glycolipids, glycosylated natural products, and other sugar-containing entities. However, a trehalose 6-phosphate synthase-like protein has been found to catalyze an unprecedented non-glycosidic C-N bond formation in the biosynthesis of the aminocyclitol antibiotic validamycin A. This dedicated ‘pseudoglycosyltransferase’ catalyzes a condensation between GDP-valienol and validamine 7-phosphate to give validoxylamine A 7′-phosphate with net retention of the ‘anomeric’ configuration of the donor cyclitol in the product. The enzyme operates in sequence with a phosphatase, which dephosphorylates validoxylamine A 7′-phosphate to validoxylamine A.

Validamycin A is a member of microbial-derived C7N-aminocyclitol family of natural products that is widely used as crop protectant and the precursor of the antidiabetic drug voglibose. Its biosynthetic gene clusters have been identified in several Streptomyces hygroscopicus strains, and a number of genes within the clusters have been functionally analyzed. Of these genes, valB, which encodes a sugar nucleotidyltransferase, was found through inactivation study to be essential for validamycin biosynthesis, but its role was unclear. To characterize the role of ValB in validamycin biosynthesis, four carbasugar phosphate analogues were synthesized and tested as substrate for ValB. The results showed that ValB efficiently catalyzes the conversion of valienol 1-phosphate to its nucleotidyl diphosphate derivatives, whereas other unsaturated carbasugar phosphates were found to be not the preferred substrate. ValB requires Mg2+, Mn2+, or Co2+ for its optimal activity and uses the purine-based nucleotidyltriphosphates (ATP and GTP) more efficiently than the pyrimidine-based NTPs (CTP, dTTP, and UTP) as nucleotidyl donor. ValB represents the first member of unsaturated carbasugar nucleotidyltransferases involved in natural products biosynthesis. Its characterization not only expands our understanding of aminocyclitol-derived natural products biosynthesis, but may also facilitate the development of new tools for chemoenzymatic synthesis of carbohydrate mimetics.

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Solandelactones A, B, E, and F were synthesized using Nozaki-Hiyama-Kishi coupling of iododiene 13 with aldehydes 14 and 99 obtained by oxidation of alcohols 92 and 94. Key steps in the synthesis of 92 and 94 were (i) a Nagao asymmetric acetate aldol reaction of aldehyde 77 with thionothiazolidine 78 to set in place an alcohol that becomes the (7 S) lactone center of solandelactones, (ii) a Simmons-Smith cyclopropanation of 80 directed by this alcohol, and (iii) Petasis methylenation of cyclic carbonate 90 in tandem with a Claisen rearrangement that generates the octenalactone portion of solandelactones. Synthesis of solandelactones A, B, E, and F confirmed their gross structure and absolute configuration at C7, 8, 10, and 14 but showed that alcohol configuration at C11 must be reversed in pairs, A/B and E/F, from the previous assignment made to these hydroid metabolites. Thus, solandelactones A and B are correctly represented by 2 and 1, respectively, whereas solandelactones E and F are 6 and 5. A biogenesis of solandelactones is proposed for these C 22 oxylipins that parallels a hypothesis put forward previously to explain the origin of C 20 cyclopropane-containing algal products.