Discovery of Efrotomycin Congeners and Heterologous Expression-Based Insights into the Self-Resistance Mechanism

Abstract

Four new efrotomycins, A1–A4 (1–4), were isolated from the salt mine-derived Amycolatopsis cihanbeyliensis DSM 45679 and structurally determined. Efrotomycins A3 (3) and A4 (4) feature a tetrahydrofuran ring configured distinctly from known elfamycins. Heterologous expression of the efrotomycin gene cluster (efr BGC) in Streptomyces lividans SBT18 led to efrotomycin B1 (5), the yield of which was improved several fold upon introduction of the transporter gene efrT, a putative self-resistance determinant outside of the efr BGC.

Discovery and Biosynthesis of Cihanmycins Reveal Cytochrome P450-Catalyzed Intramolecular C–O Phenol Coupling Reactions

“…A. cihanbeyliensis DSM 45679 was previously reported to produce new efrotomycins . A careful high-performance liquid chromatography–high-resolution mass spectrometry (HPLC-HRMS) analysis of the product profile of A.…”

“…cihanbeyliensis DSM 45679 36 was previously reported to produce new efrotomycins. 37 A careful high-performance liquid chromatography−high-resolution mass spectrometry (HPLC-HRMS) analysis of the product profile of A. cihanbeyliensis DSM 45679 revealed the presence of additional metabolites other than efrotomycins (Figure S2). Subsequently, 15 L scale cultures of A. cihanbeyliensis DSM 45679 were performed to warrant the isolation of two new bicyclic CCNPs CHMs A (1) and B (2) (Figure 1).…”