Late-stage cascade of oxidation reactions during the biosynthesis of oxalicine B in Penicillium oxalicum

Oxalicine B(1)is an a-pyrone meroterpenoid with a unique bispirocyclic ring system derived from Penicillium oxalicum.The biosynthetic pathway of 15-deoxyoxalicine B(4)was preliminarily reported in Penicillium canescens,however,the genetic base and biochemical characterization of tailoring reactions for oxalicine B(1)has remained enigmatic.In this study,we characterized three oxygenases from the metabolic pathway of oxalicine B(1),including a cytochrome P450 hydroxylase OxaL,a hydroxylating Fe(II)/a-KG-dependent dioxygenase OxaK,and a multifunctional cytochrome P450 OxaB.Intriguingly,OxaK can catalyze various multicyclic intermediates or shunt products of oxalicines with impressive substrate promiscuity.OxaB was further proven via biochemical assays to have the ability to convert 15-hydroxdecaturin A(3)to 1 with a spiro-lactone core skeleton through oxidative rearrangement.We also solved the mystery of OxaL that controls C-15 hydroxylation.Chemical investigation of the wild-type strain and deletants enabled us to identify 10 metabolites including three new compounds,and the isolated compounds displayed potent anti-influenza A virus bioactivities exhibiting IC50values in the range of 4.0-19.9μmol/L.Our studies have allowed us to propose a late-stage biosynthetic pathway for oxalicine B(1)and create downstream derivatizations of oxalicines by employing enzymatic strategies.

Cyclic and Linear Thiopeptides from Soil-Derived Streptomyces sp.CPCC 203702 with Antiviral and Antibacterial Activities

A new cyclic thiopeptide,berninamycin F(3),three new linear thiopeptides,berninamycins G—I(4-6),and two known berninamycin derivatives,berninamycins C and D(1 and 2)were isolated from Streptomyces sp.CPCC 203702.Their structures were elucidated through HRESIMS and one-and two-dimensional NMR data,and the absolute configurations were assigned using Marfey's method.Compounds 4-6 are the first examples of linear berninamycin analogs.Notably,compound 4 is the first example of linear thiopeptide with a 1-(oxazol-2-yl)ethan-1-one group,compound 6 is the first linear thiopeptide derivative with methylated oxoacetate moiety.Compounds 1-6 exhibited excellent anti-Zika virus activities with IC_(50) values in the range of 4.4-10.5μmol/L,which were superior to that of the positive control ribavirin(IC_(50)=49.2μmol/L).Compounds 1 and 3 showed strong anti-influenza A virus activities with the IC_(50) values of 15.6 and 3.2μmol/L,respectively.Compound 1 exhibited good antibacterial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.pathogens.