摘要：SummaryHeterologous expression of a biosynthesis gene cluster fromAmycolatopsissp. resulted in the discovery of two unique class IV lasso peptides, felipeptins A1 and A2. A mixture of felipeptins stimulated proliferation of cancer cells, while having no such effect on the normal cells. Detailed investigation revealed, that pre-treatment of cancer cells with a mixture of felipeptins resulted in downregulation of the tumor suppressor Rb, making the cancer cells to proliferate faster. Pre-treatment with felipeptins made cancer cells considerably more sensitive to the anticancer agent doxorubicin and re-sensitized doxorubicin-resistant cells to this drug. Structural characterization and binding experiments showed an interaction between felipeptins resulting in complex formation, which explains their synergistic effect. This discovery may open an alternative avenue in cancer treatment, helping to eliminate quiescent cells that often lead to cancer relapse.Graphical AbstractDisplay OmittedHighlights•Lasso peptides felipeptins fromAmycolatopsissp. produced in a heterologous host•Felipeptins synergistically sensitize cancer cells to doxorubicin•Synergistic effect on cancer cells appears to be due to complex formation•Felipeptins overcome drug resistance of cancer stem cellsBiological Sciences; Biochemistry; Microbiology; Biotechnology
