Mak Stefanie, Nodwell Justin R
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Mol Microbiol. 2017 Nov;106(4):597-613. doi: 10.1111/mmi.13837. Epub 2017 Oct 11.
Actinorhodin is a blue-pigmented, redox-active secondary metabolite that is produced by the bacterium Streptomyces coelicolor. Although actinorhodin has been used as a model compound for studying secondary metabolism, its biological activity is not well understood. Indeed, redox-active antibiotics in general have not been widely investigated at the mechanistic level. In this work, we have conducted a comprehensive chemical genetic investigation of actinorhodin's antibacterial effect on target organisms. We find that actinorhodin is a potent, bacteriostatic, pH-responsive antibiotic. Cells activate at least three stress responses in the presence of actinorhodin, including those responsible for managing oxidative damage, protein damage and selected forms of DNA damage. We find that mutations in the Staphylococcus aureus walRKHI operon can confer low-level resistance to actinorhodin, indicating possible targeting of the cell envelope. Our study indicates a complex mechanism of action, involving multiple molecular targets, that is distinct from other antibiotics.
放线紫红素是一种由天蓝色链霉菌产生的蓝色色素、具有氧化还原活性的次级代谢产物。尽管放线紫红素已被用作研究次级代谢的模型化合物，但其生物活性尚未得到充分了解。事实上，一般来说，具有氧化还原活性的抗生素在作用机制层面尚未得到广泛研究。在这项工作中，我们对放线紫红素对靶标生物的抗菌作用进行了全面的化学遗传学研究。我们发现放线紫红素是一种强效、抑菌、pH响应型抗生素。在放线紫红素存在的情况下，细胞会激活至少三种应激反应，包括那些负责应对氧化损伤、蛋白质损伤和特定形式DNA损伤的反应。我们发现金黄色葡萄球菌walRKHI操纵子中的突变可赋予对放线紫红素的低水平抗性，这表明其可能靶向细胞壁。我们的研究表明其作用机制复杂，涉及多个分子靶点，这与其他抗生素不同。
