NYU and Janssen Develop New Class of Proteins to Fight Antibiotic-Resistant Infections

纽约大学和杨森制药开发新型工程蛋白,对抗引起金黄色葡萄球菌感染的细菌

2019-01-22 07:20:00 BioSpace

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Staphylococcus aureus infection.  Researchers at New York University School of Medicine and Janssen Research & Development, a Johnson & Johnson company, have developed a new class of engineered proteins that may help fight the bacteria that cause Staph infections. The results of a five-year research partnership were published in the journal Science Translational Medicine. “To our knowledge, this is the first report showing that proteins called centyrins can potentially block the effects of severe S. aureus bacterial infections in mice, and in human cell experiments,” stated lead author Victor Torres, associate professor in the Department of Microbiology at NYU Langone Health. The researchers identified a group of centyrins that blocked the action of five toxins generated by Staphylococcus aureus, the bacteria that causes Staph infections. These five toxins are used by the bacteria to evade the human immune system. The centyrins don’t destroy the germs but take away their ability to thrive. This new approach has the potential to deal with antibiotic resistance. A January 2018 report by the World Health Organization (WHO)’s Global Antimicrobial Surveillance System (GLASS), found widespread antibiotic resistance among 500,000 people with suspected bacterial infections in 22 countries. The most commonly reported bacteria resistant to antibiotics were Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae, followed by Salmonella species. Marc Springer, director of WHO’s Antimicrobial Resistance Secretariat, stated at the time, “The report confirms the serious situation of antibiotic resistance worldwide. Some of the world’s most common—and potentially most dangerous—infections are proving drug-resistant. And most worrying of all, pathogens don’t respect national borders. That’s why WHO is encouraging all countries to set up good surveillance systems for detecting drug resistance that can provide data to this global system.” About a third of all people around the world are carriers of S. aureus, typically without symptoms. But in people with weakened immune systems, S. aureus can cause serious, life-threatening infections in the lung, heart, bone or bloodstream. Staph infections are a serious problem in hospitals, where because of widespread use of antibiotics, especially methicillin, methicillin-resistant S. aureus (MRSA) infections cause 11,000 deaths in the U.S. annually. In 1998, researchers, including NYU’s Shohei Koide, discovered a class of proteins that came from fibronectin type III (FN3) protein subunits. They were originally classified as monobodies and investigated as cancer treatments by Janssen researchers. Centyrins are FN3 “scaffolds” optimized for drug development, and eventually, Janssen used them to as anti-toxins. The toxins produced by S. aureus, such as leucocidin AB, which was identified by Torres’ laboratory, drill holes in immune cells, killing them before they can kill the bacteria. They also drill into red blood cells, flooding bacteria with nutrients. The researchers in this study used molecular techniques and automation to change a single parental centyrin, which created a trillion slightly modified centyrins. They screened the library and found 209 centyrins that bind to pieces of one of the five major S. aureus leukotoxins. In human cells, they found that the ones that bound the tightest could prevent the toxins from attaching and destroying the cells they would otherwise drill into. Dosing mice with toxic levels of LukED S. aureus toxin, they also dosed some of the mice with the SM1S26 centyrin. The mice who didn’t receive the centyrin died, while those who did receive it lived. Even in cases where the mice received centyrin four hours after live S. aureus infection, half of the infected animals survived compared to none in the control group of infected mice. The team is now working to develop biologics that combine centyrins with anti-staphylococcal monoclonal antibodies in a new class of proteins called MABtyrins. “One of the most exciting aspects of this work is that scientists may be able to pick their pathogen, and then easily generate a vast, cost-effective library of centyrins shaped to interfere with the disease process at hand,” Torres stated. “It’s bigger than one experimental treatment.”
金黄色葡萄球菌感染. 纽约大学医学院( NewYorkUniversity School of Medicine )和强生( Johnson & Johnson )公司杨森制药 Research & Development 的研究人员已经开发出一种新型的工程蛋白,可以帮助对抗导致葡萄球菌感染的细菌。 五年研究合作的结果发表在《科学转化医学》杂志上。“据我们所知,这是第一份报告,它显示被称为半酪蛋白的蛋白质有可能阻止严重的 S 。金葡菌在小鼠和人体细胞实验中的感染,”作者维克多·托雷斯( VictorTorres )说,他是 NYU Langon Health 微生物学系的副教授。 研究人员确定了一组半酪蛋白,它们阻断了金黄色葡萄球菌(引起葡萄球菌感染的细菌)产生的五种毒素的作用。这五种毒素被细菌用来逃避人类免疫系统。半暴君不会破坏细菌,而是剥夺了它们茁壮成长的能力。这种新方法有可能处理抗生素耐药性。 世界卫生组织(世卫组织)全球抗生素监测系统( GLASS )2018年1月的一份报告发现,在22个国家的50万疑似细菌感染患者中,抗生素耐药性普遍存在。最常见的抗生素耐药性报告的细菌是金黄色葡萄球菌、大肠杆菌、肺炎克雷伯杆菌和肺炎链球菌,其次是沙门氏菌。 世卫组织抗微生物耐药性秘书处主任 MarcSpringer 当时表示,“该报告证实了全球抗生素耐药性的严重状况。世界上一些最常见的——也可能是最危险的——感染被证明具有耐药性。最令人担忧的是,病原体不尊重国界。这就是为什么世卫组织鼓励所有国家建立检测耐药性的良好监测系统,为这个全球系统提供数据。” 全世界大约三分之一的人都是 S 。金葡菌,通常没有症状,但在免疫系统减弱的人, S 。金葡菌可导致严重的,危及生命的感染在肺部,心脏,骨骼或血液。在医院中,葡萄球菌感染是一个严重的问题,因为抗生素的广泛使用,尤其是甲氧西林,耐甲氧西林金黄色葡萄球菌( MRSA )感染每年在美国造成11000人死亡。 1998年,包括纽约大学的 ShoheiKoide 在内的研究人员发现了一类来自纤维连接蛋白 III 型( FN3)蛋白亚单位的蛋白质。他们最初被归为单身体,并被杨森制药的研究人员调查为癌症治疗。Centyrin 是 FN3“支架”,用于药物开发,最终杨森制药将其用作抗毒素。 由 S 产生的毒素。金葡菌,如 Torres 实验室鉴定的白细胞 AB ,在免疫细胞上钻孔,在杀死细菌之前杀死它们。他们还会钻进红血球中,用营养物质把细菌淹没. 本研究的研究人员使用分子技术和自动化技术来改变一个亲本的半乳酪蛋白,它产生了一万亿个稍微修改的半乳酪蛋白。他们对图书馆进行了筛选,发现了209个与五个主要的 S 。金葡白耳毒素。在人类细胞中,他们发现那些结合最紧密的细胞可以防止毒素附着和破坏它们原本钻进的细胞。 用有毒的 LukedS 剂量小鼠。金葡毒素,他们也给一些小鼠注射了 SM1S26半酪氨酸。没有接受半暴君的老鼠死了,而接受半暴君的老鼠活了下来。即使是在老鼠在存活四个小时后接受半酪蛋白的情况下。金葡菌感染后,半数受感染的动物存活下来,而对照组则无感染。 该团队目前正在开发一种生物制剂,将半酪蛋白与抗葡萄球菌单克隆抗体结合在一种名为 MAB酪氨酸的新型蛋白质中。 “这项工作最令人兴奋的一个方面是,科学家可能能够挑选出他们的病原体,然后很容易产生一个巨大的、具有成本效益的半胱氨酸文库,这种文库的形状干扰了目前的疾病过程,”托雷斯说。“它比一种实验疗法更大。”

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