Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
Microbiol Spectr. 2019 Jul;7(4). doi: 10.1128/microbiolspec.GPP3-0063-2019.
Diphtheria is one of the most well studied of all the bacterial infectious diseases. These milestone studies of toxigenic along with its primary virulence determinant, diphtheria toxin, have established the paradigm for the study of other related bacterial protein toxins. This review highlights those studies that have contributed to our current understanding of the structure-function relationships of diphtheria toxin, the molecular mechanism of its entry into the eukaryotic cell cytosol, the regulation of diphtheria expression by holo-DtxR, and the molecular basis of transition metal ion activation of apo-DtxR itself. These seminal studies have laid the foundation for the protein engineering of diphtheria toxin and the development of highly potent eukaryotic cell-surface receptor-targeted fusion protein toxins for the treatment of human diseases that range from T cell malignancies to steroid-resistant graft-versus-host disease to metastatic melanoma. This deeper scientific understanding of diphtheria toxin and the regulation of its expression have metamorphosed the third-most-potent bacterial toxin known into a life-saving targeted protein therapeutic, thereby at least partially fulfilling Paul Erlich's concept of a magic bullet-"a chemical that binds to and specifically kills microbes or tumor cells."
白喉是所有细菌性传染病中研究得最透彻的疾病之一。这些关于产毒菌及其主要毒力决定因子白喉毒素的里程碑式研究，为研究其他相关的细菌蛋白毒素确立了范例。本综述重点介绍了那些有助于我们当前理解白喉毒素结构-功能关系、其进入真核细胞质的分子机制、全毒素结合蛋白（holo-DtxR）对白喉毒素表达的调控以及金属离子激活apo-DtxR 自身的分子基础的研究。这些开创性的研究为白喉毒素的蛋白质工程以及开发高效的真核细胞表面受体靶向融合蛋白毒素奠定了基础，这些毒素可用于治疗从 T 细胞恶性肿瘤到类固醇耐药移植物抗宿主病再到转移性黑色素瘤等人类疾病。对白喉毒素及其表达调控的更深入的科学认识，已经将已知第三强效的细菌毒素转化为一种救命的靶向蛋白治疗药物，从而至少部分实现了保罗·埃尔利希（Paul Ehrlich）的“魔术子弹”概念——“一种与微生物或肿瘤细胞结合并特异性杀死它们的化学物质”。
