Demonstration of N,N-Dimethyldithiocarbamate as a Copper-Dependent Antibiotic against Multiple Upper Respiratory Tract Pathogens.
Demonstration of N,N-Dimethyldithiocarbamate as a Copper-Dependent Antibiotic against Multiple Upper Respiratory Tract Pathogens.
复制标题
N，N-二甲基二硫代氨基甲酸盐作为抗多种上呼吸道病原体的铜依赖性抗生素的证明。
DOI：
10.1128/spectrum.00778-21
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发表时间：
2021-10-31
影响因子：
3.7
通讯作者：
Johnson MDL
中科院分区：
文献类型：
--
作者：
Menghani SV;Rivera A;Neubert M;Hagerty JR;Lewis L;Galgiani JN;Jolly ER;Alvin JW;Johnson MDL
过渡金属是生命系统中必不可少的辅因子和结构元素。暴露于高浓度的具有重要生物学意义的过渡金属，如锌和铜，会导致细胞毒性。在感染部位，免疫系统部署金属吸附蛋白（如乳铁蛋白和钙保护蛋白）使病原体缺乏必要的金属（如铁），而吞噬细胞则使被吞噬的病原体暴露于高水平的其他金属，如铜和锌。机会致病菌肺炎链球菌（肺炎球菌）在初次感染和长期感染期间遇到巨噬细胞。肺炎球菌采用铜输出途径，这改善了鼻咽和上呼吸道的定植和持续感染。由于铜在宿主体内受到严格调控，我们转而寻求利用营养免疫的局部力量，通过靶向筛选具有铜依赖性毒性（CDT）的小分子来获得抗生素疗效。我们选择包括二硫代氨基甲酸酯，基于在其他生物体中观察到的铜与1-（二乙基硫代氨基乙基二磺胺）- n， n -二乙基甲乙酰胺（四乙基硫代氨基二磺胺，二磺胺）的协同作用。我们观察到一些二硫代氨基甲酸酯在肺炎链球菌中的CDT。在体内和体外，只有N，N-二甲基二硫代氨基甲酸酯（DMDC）在铜的浓度范围内对肺炎球菌具有一致的毒性。我们还使用DMDC在体外观察了金黄色葡萄球菌、波萨达孢子虫和曼氏血吸虫不同程度的CDT。总之，我们证明了化合物DMDC是一种有效的杀菌化合物，对肺炎链球菌具有抗菌作用，对细菌和真菌病原体具有抗菌作用。随着抗生素耐药性的上升，在现有抗生素储备中增加新的抗微生物药物的方法至关重要。在这里，我们研究了假设的和已知的铜离子载体，试图利用离子载体/铜协同作用来使细菌中毒，我们最终发现N，N-二甲基二硫代氨基甲酸盐（DMDC）取得了成功。我们表明，DMDC具有铜依赖的体外功效，可以杀死三种不同的病原体，肺炎链球菌、波萨达球虫和曼氏血吸虫，以及体内对肺炎链球菌的功效。因此，二硫代氨基甲酸酯代表了一类新的潜在抗菌剂，因此值得进一步的机制研究。
Transition metals are necessary cofactors and structural elements in living systems. Exposure to high concentrations of biologically important transition metals, such as zinc and copper, results in cell toxicity. At the infection site, the immune system deploys metal sorbent proteins (e.g., lactoferrin and calprotectin) to starve pathogens of necessary metals (such as iron), while phagocytes expose engulfed pathogens to high levels of other metals, such as copper and zinc. The opportunistic pathogen Streptococcus pneumoniae (the pneumococcus) encounters macrophages during initial and protracted infections. The pneumococcus employs a copper export pathway, which improves colonization and persistent infection of the nasopharynx and the upper respiratory tract. Because copper is tightly regulated in the host, we instead sought to leverage the localized power of nutritional immunity by identifying small molecules with copper-dependent toxicity (CDT) through a targeted screen of compounds for antibiotic efficacy. We chose to include dithiocarbamates, based on the copper synergy observed in other organisms with 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide (tetraethylthiuram disulfide, disulfiram). We observed CDT of some dithiocarbamates in S. pneumoniae. Only N,N-dimethyldithiocarbamate (DMDC) was consistently toxic across a range of concentrations with copper both in vitro and in vivo against the pneumococcus. We also observed various degrees of CDT in vitro using DMDC in Staphylococcus aureus, Coccidioides posadasii, and Schistosoma mansoni. Collectively, we demonstrate that the compound DMDC is a potent bactericidal compound against S. pneumoniae with antimicrobial efficacy against bacterial and fungal pathogens. IMPORTANCE With the rise of antibiotic resistance, approaches that add new antimicrobials to the current repertoire are vital. Here, we investigate putative and known copper ionophores in an attempt to intoxicate bacteria and use ionophore/copper synergy, and we ultimately find success with N,N-dimethyldithiocarbamate (DMDC). We show that DMDC has in vitro efficacy in a copper-dependent manner and kills pathogens across three different kingdoms, Streptococcus pneumoniae, Coccidioides posadasii, and Schistosoma mansoni, and in vivo efficacy against S. pneumoniae. As such, dithiocarbamates represent a new potential class of antimicrobials and thus warrant further mechanistic investigation.