Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States.
Bioorg Med Chem Lett. 2019 May 1;29(9):1106-1112. doi: 10.1016/j.bmcl.2019.02.028. Epub 2019 Feb 28.
All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
所有生物体都含有一类独特的分子伴侣，称为 60kDa 热休克蛋白（HSP60-也称为细菌中的 GroEL）。虽然有些生物体含有一种以上的 HSP60 或 GroEL 同工型，但至少有一种同工型始终被证明是必不可少的。因此，我们一直在研究将 HSP60 和 GroEL 伴侣蛋白系统作为一种抗生素策略。我们的初步研究集中在应用这种抗生素策略来治疗非洲昏睡病（由布氏锥虫寄生虫引起）和耐药细菌感染（特别是耐甲氧西林金黄色葡萄球菌-MRSA）。有趣的是，在我们的研究过程中，我们发现三种已知的抗生素-苏拉明、氯硝柳胺和硝呋莫司-是细菌 GroEL 和人 HSP60 伴侣蛋白系统的有效抑制剂。这些发现促使我们探索其他已批准的药物、天然产物和已知的生物活性分子是否也能抑制 HSP60 和 GroEL 伴侣蛋白系统。对 3680 种已批准的药物、天然产物和已知生物活性物质进行的初始高通量筛选，确定了 161 种大肠杆菌 GroEL 伴侣蛋白系统的抑制剂（4.3%的命中率）。在购买的 60 个命中物中，有 29 个化合物（48%）在我们的测定中重新被确认为选择性 GroEL 抑制剂，所有这些化合物对人 HSP60 的抑制作用几乎相同。这些发现阐明了这样一种观点，即靶向伴侣蛋白系统可能比我们以前认为的更为常见。需要进一步的研究来确定这些已批准的药物、天然产物和已知生物活性分子的体内作用模式是否与 GroEL 和 HSP60 的抑制有关。
