Activation of the Trichodimerol Pathway through Deletion of <i>mcrA</i> in Marine <i>Penicillium rubens</i> YAP001

Fungal secondary metabolites (SMs) are complex organic compounds comprising a variety of biological activities that are essential in medicine. These natural products can be found in various environments, with studies demonstrating the importance of studying marine-sourced fungi due to the increased potency of the compounds they produce. In this study, we sourced a <i>Penicillium rubens</i> YAP001 strain isolated from <i>Exaiptasia diaphana</i> and explored an avenue for the upregulation of its SMs by combining the one-strain-many-compounds (OSMAC) strategy with genetic manipulation of negative global regulator of secondary metabolism, <i>mcrA</i>. Here, we generated a <i>mcrA</i>Δ strain of marine <i>P. rubens</i> (YAP001), which led to the detection of sorbicillinoids, which is significant due to the prior discovery that these compounds illicit cytotoxic effects that have the potential as an anticancer agent. Specifically, we found that sorbicillin was not only upregulated but the mutant strain also produced the dimeric product, trichodimerol, which often exhibits stronger biological activities compared to sorbicillin. Furthermore, the reduced form of trichodimerol, dihydrotrichodimerol, was also detected in the mutant strain. This work suggests that genetic manipulation of global regulators in combination with the OSMAC method in filamentous fungi is a promising technique for upregulating pathways of interest for small-molecule drug discovery.