N,N-Dimethyldithiocarbamate Elicits Pneumococcal Hypersensitivity to Copper and Macrophage-Mediated Clearance.
N,N-Dimethyldithiocarbamate Elicits Pneumococcal Hypersensitivity to Copper and Macrophage-Mediated Clearance.
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DOI：
10.1128/iai.00597-21
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发表时间：
2022-04-21
影响因子：
3.1
通讯作者：
中科院分区：
文献类型：
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作者：
肺炎链球菌是一种革兰氏阳性、被包裹的细菌，是儿童和老年人口疾病负担的重要原因。肺炎链球菌中无包膜致病菌株和抗菌素耐药性的增加增加了开发新的抗菌素策略的必要性。我们实验室最近的工作发现，N，N-二甲基二硫代氨基甲酸酯(DMDC)是一种铜依赖的抗菌剂，对细菌、真菌和寄生虫具有抑制作用。作为一种抗肺炎链球菌的杀菌抗生素，DMDC作为铜依赖抗生素的作用能力以及它在体内的作用能力值得进一步研究。在这里，我们的团队研究了DMDC在不同介质和过量金属条件下的作用机制，并研究了DMDC与体内和体外天然免疫系统的相互作用。值得注意的是，我们发现DMDC加铜可显著增加体内铜浓度、过氧化氢应激、一氧化氮应激，以及体外巨噬细胞杀伤效率，并降低胶囊。此外，我们还发现，在体内，DMDC治疗增加了感染期间肺内天然免疫细胞的数量。综上所述，这项研究提供了关于DMDC在宿主-病原体界面作为抗生素的活性的机械性见解。
Streptococcus pneumoniae is a Gram-positive, encapsulated bacterium that is a significant cause of disease burden in pediatric and elderly populations. The rise in unencapsulated disease-causing strains and antimicrobial resistance in S. pneumoniae has increased the need for developing new antimicrobial strategies. Recent work by our laboratory has identified N,N-dimethyldithiocarbamate (DMDC) as a copper-dependent antimicrobial against bacterial, fungal, and parasitic pathogens. As a bactericidal antibiotic against S. pneumoniae, DMDC’s ability to work as a copper-dependent antibiotic and its ability to work in vivo warranted further investigation. Here, our group studied the mechanisms of action of DMDC under various medium and excess-metal conditions and investigated DMDC’s interactions with the innate immune system in vitro and in vivo. Of note, we found that DMDC plus copper significantly increased the internal copper concentration, hydrogen peroxide stress, nitric oxide stress, and the in vitro macrophage killing efficiency and decreased capsule. Furthermore, we found that in vivo DMDC treatment increased the quantity of innate immune cells in the lung during infection. Taken together, this study provides mechanistic insights regarding DMDC’s activity as an antibiotic at the host-pathogen interface.
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DOI：
10.1073/pnas.2015368117
发表时间：
2020-12-29
影响因子：
11.1
作者：
Inomata M;Xu S;Chandra P;Meydani SN;Takemura G;Philips JA;Leong JM
通讯作者：
Leong JM
影响因子：
32.4
作者：
Califano D;Cho JJ;Uddin MN;Lorentsen KJ;Yang Q;Bhandoola A;Li H;Avram D
通讯作者：
Avram D
影响因子：
3.4
作者：
Johnson, Michael D. L.;Kehl-Fie, Thomas E.;Rosch, Jason W.
通讯作者：
Rosch, Jason W.
影响因子：
3.1
作者：
Johnson, Michael D. L.;Kehl-Fie, Thomas E.;Rosch, Jason W.
通讯作者：
Rosch, Jason W.
影响因子：
4.8
作者：
Fan, B;Rosen, BP
通讯作者：
Rosen, BP