Targeted accumulation of selective anticancer depsipeptides by reconstructing the precursor supply in the neoantimycin biosynthetic pathway

Abstract Background Neoantimycins are a group of 15-membered ring depsipeptides isolated from Streptomycetes with broad-spectrum anticancer activities. Neoantimycin biosynthesis is directed by the hybrid multimodular megaenzymes non-ribosomal peptide synthetase and polyketide synthase. We previously discovered new neoantimycin analogue unantimycin B, which was demonstrated to have selective activities produced biosynthetic pathway starter unit 3-hydroxybenzoate, instead 3-formamidosalicylate that common for neoantimycins. However, low fermentation titre tough isolation procedure hindered in-depth pharmacological investigation B as an agent. Results In this work, we genetically constructed two producer strains inhibited neoantimycins production removing nat O J-L genes essential biosynthesis, therefore facilitating chromatographic separation complex extract. Based on Δ mutant, improved twofold, reaching approximately 12.8 mg/L, feeding 3-hydroxybenzoate during fermentation. Furthermore, more than sixfold, 40.0 in strain introduced chorismatase gene highly expressed under strong promoter endogenously over-producing 3-hydroxybenzoate. Conclusion This work provides case targeting accumulation significant improvement medicinally interesting natural products via genetic manipulation precursor , talented producers pharmaceutical molecules.