Heterologous biosynthetic crosstalk with the native mansouramycin cluster in <i>Streptomyces albus</i> Del14 reveals unexpected metabolites

<i>Streptomyces albus</i> J1074 (now <i>S. albidoflavus</i> J1074) is a widely used heterologous host for natural product discovery due to its capacity to express biosynthetic gene clusters (BGCs) from diverse organisms. A derivative of this strain, <i>S. albus</i> Del14, enhances heterologous expression by reducing background metabolite production enabling the identification of the previously hidden BGC responsible for producing mansouramycins. In this study, we demonstrate the biosynthetic crosstalk between the native mansouramycin BGC in <i>S. albus</i> Del14 and introduced BGCs from three different organisms results in the production of novel compounds, some featuring rare and complex chemical scaffolds. These include malevonin, which combines NRPS- and mansouramycin-derived building blocks forming a fluorene scaffold, as well as 5'-chloromansouramycin D, a halogenated derivative of mansouramycin D. Additionally, we identified mansevorone, a compound structurally similar to mansouramycin D but utilizing a different tryptophan-derived C7 precursor. This precursor likely arises from the activation of native genes in the host <i>S. albus</i> Del14, triggered by SARP regulators present on the introduced BGC. These findings highlight the evolutionary significance of BGC interactions and underscore their potential as a powerful tool for discovering novel natural products, providing insights that could inform innovative strategies in biosynthetic engineering and the guided evolution of new bioactive compounds.