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Abstract
Bafilomycin A1 is the representative compound of the plecomacrolide natural product family. This 16-membered ring plecomacrolide has potent antifungal and vacuolar H+-ATPase inhibitory activities. In our previous work, we identified a bafilomycin biosynthetic gene cluster (baf) from the marine bacterium Streptomyces lohii ATCC BAA-1276, wherein a luxR family regulatory gene orf1 and an afsR family regulatory gene bafG were revealed based on bioinformatics analysis. In this study, the positive regulatory roles of orf1 and bafG for bafilomycin biosynthesis are characterized through gene inactivation and overexpression. Compared to the wild-type S. lohii strain, the knockout of either orf1 or bafG completely abolished the production of bafilomycins. The overexpression of orf1 or bafG led to 1.3- and 0.5-fold increased production of bafilomycins, respectively. A genetically engineered S. lohii strain (SLO-08) with orf1 overexpression and inactivation of the biosynthetic genes orf2 and orf3, solely produced bafilomycin A1 with the titer of 535.1 ± 25.0 mg/L in an optimized fermentation medium in shaking flasks. This recombinant strain holds considerable application potential in large-scale production of bafilomycin A1 for new drug development.
Highlights
Bafilomycins, which are mainly produced by Streptomyces, belong to the plecomacrolide (i.e., a 16- or 18-membered macrolactone connected to a 6-membered hemiacetal ring via a three-carbon linker) subfamily of polyketide natural products
Soybean oil has been used as a low-cost feedstock to enhance the supply of biosynthetic precursors for improvement of polyketide production in Streptomyces since fatty acids can be directly bioconverted into acyl-CoAs as the precursors of polyketides [24,44,45]
The FK506 production in Streptomyces tsukubaensis was increased 0.9-fold by feeding soybean oil into the production medium [24]
Summary
Bafilomycins, which are mainly produced by Streptomyces, belong to the plecomacrolide (i.e., a 16- or 18-membered macrolactone connected to a 6-membered hemiacetal ring via a three-carbon linker) subfamily of polyketide natural products. Bafilomycin A1 was recently reported to be capable of interrupting the function of the viral receptor ACE2 via inhibiting the V-ATPase, being considered as a candidate for treating the infections caused by coronaviruses (e.g., COVID-19, SARS-CoV, and MERSCoV) [15] Despite these promising results, such a potent drug candidate has not entered clinical application owing to its high toxicity to mammalian cells [16]. Tion of the viraTlhreecCe5pNtorunAiCt Eis2avsisaeminbhliebditibnyg tthhee aVc-yAl-TCPoaAse,litghausse bBeainfXg acnondsitdheerebdifuanscational enzyme candidate for tBreaafZtin[g9,2th0e].infections caused by coronaviruses (e.g., COVID-19, SARS-CoV, and MERS-CoV) [15] SreaclRepIItIo[r4f0o]r, PinimduMce[r4b1i]n, danindgF[s3c9R],Is[u4c2h].aHs othweePver-,AOrrnft1-Soinmly(PhAasS)adCo-mtearminisnoafl SHaTlRHIIIm[o40ti]f, aPsimGMerE[,4s1u],gganesdtinFgsctRhIat[4O2r]f.1Hmoigwhetvbeer,aOn rinf1duoncelyr-ihnadsepaeCn-dternmt LinuaxlRHhToHmomloogtuifeacsapGaebrlEe, osuf gdgireescttinlygatchtaitvOatrinf1gmthigehttrabnesacnriipntdiounceorf-irnedlaetpeedngdenet sLuasxRthheoNm-otrluognucaetceadpLabulxeRof(∆d2ir–e1c6t2ly) [a4c3t]iv. ating the transcription of related genes as the N-truncated LuxR (∆2–162) [43]
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