Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens.
Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens.
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DOI：
10.1038/srep22571
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发表时间：
2016-03-03
影响因子：
4.6
通讯作者：
Seleem MN
中科院分区：
文献类型：
--
作者：
Thangamani S;Mohammad H;Abushahba MF;Sobreira TJ;Hedrick VE;Paul LN;Seleem MN
用于发现新抗生素的传统方法既耗时又费钱。这导致研究人员挖掘现有的临床分子库，以便将旧药物重新用于新的应用（作为抗菌剂）。这样的努力导致了金诺芬的发现，金诺芬是一种最初被批准为抗风湿药的药物，在临床可实现的范围内也具有强效抗菌活性。目前的研究表明，金诺芬的抗菌活性是一个复杂的过程，涉及抑制多种生物合成途径，包括细胞壁，DNA和细菌蛋白质合成。我们还证实，所观察到的金诺芬对革兰氏阴性菌的活性的缺乏是由于外膜赋予的渗透性屏障。金诺芬抑制细菌蛋白质合成的能力导致关键耐甲氧西林金黄色葡萄球菌（MRSA）毒素的产生显著减少。此外，金诺芬能够根除感染的巨噬细胞内存在的细胞内MRSA。此外，金诺芬在MRSA全身感染的小鼠模型中是有效的，并且显著降低了包括脾和肝的鼠器官中的细菌负荷。总的来说，这项研究提供了有价值的证据，表明金诺芬有可能被重新用作治疗侵袭性细菌感染的新型抗菌药物。
Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin’s antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin’s ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections.