Department of Biothecnology, Centro de Investigaciones Biológicas Margarita Salas, Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain.
Research and Development Department, PharmaMar S.A., 28770 Madrid, Spain.
Mar Drugs. 2024 Sep 13;22(9):418. doi: 10.3390/md22090418.
PMA22 produces safracins, a family of compounds with potent broad-spectrum anti-bacterial and anti-tumor activities. The safracins' biosynthetic gene cluster (BGC sac) consists of 11 ORFs organized in two divergent operons ( and ) that are controlled by and promoters. Contiguous to the BGC sac, we have located a gene that encodes a putative global regulator of the LysR family annotated as MexT that was originally described as a transcriptional activator of the MexEF-OprN multidrug efflux pump in . Through both in vitro and in vivo experiments, we have demonstrated the involvement of the dual regulatory system MexT-MexS on the BGC sac expression acting as an activator and a repressor, respectively. The MexEF-OprN transport system of PMA22, also controlled by MexT, was shown to play a fundamental role in the metabolism of safracin. The overexpression of in PMA22 resulted in fourfold higher production levels of safracin. These results illustrate how a pleiotropic regulatory system can be critical to optimizing the production of tailored secondary metabolites, not only through direct interaction with the BGC promoters, but also by controlling their transport.
PMA22 产生沙福菌素，这是一类具有广谱抗菌和抗肿瘤活性的化合物。沙福菌素的生物合成基因簇（BGC sac）由 11 个 ORF 组成，分为两个发散的操纵子（和），由和启动子控制。在 BGC sac 附近，我们定位了一个基因，该基因编码一个假定的 LysR 家族全局调节剂，被注释为 MexT，最初被描述为在中的 MexEF-OprN 多药外排泵的转录激活物。通过体外和体内实验，我们证明了 MexT-MexS 双调控系统参与了 BGC sac 表达，分别作为激活子和抑制剂发挥作用。PMA22 的 MexEF-OprN 转运系统也受 MexT 控制，它在沙福菌素代谢中起着至关重要的作用。在 PMA22 中过表达，导致沙福菌素的产量提高了四倍。这些结果说明了多效调节系统如何通过直接与 BGC 启动子相互作用，以及通过控制其运输，对优化定制次生代谢产物的生产至关重要。
