Aversion Therapy for Bacteria: Repurposing Aurodox

抗生素已使用多年，是治疗许多常见细菌感染的核心。然而，由于抗生素会杀死细菌，因此对突变体有很强的选择性，与亲本类型的细菌略有不同，它们不会被杀死：一种新的耐药形式。这些对普通抗生素不再敏感的耐药细菌病例意味着非常需要新的替代治疗形式。在所有引起问题的细菌中，革兰氏阴性菌家族是最难治疗的，因为它们很快就会产生耐药性。一种可能性是通过关闭致病细菌的攻击性武器来降低它们的危险性。“关闭”细菌武器的化合物被称为“抗毒性”化合物，因为它们不试图杀死细菌，它们只是使它们不那么危险。想象一下，把一支军队和消除其所有的关键武器-这是一个很大的效率。使用抗毒力因子是有吸引力的，原因如下：（1）抗毒力化合物“解除”细菌的武装，而不是杀死它们，产生更少的抗性突变体的选择。(2)与抗生素治疗相关的继发性感染，如由艰难梭菌和白色念珠菌引起的感染，也应该大大减少，因为天然的“好”细菌在治疗过程中不会被消灭。(3)对于产毒细菌，传统抗生素治疗是有争议的，有一些报告说毒素释放增加，症状更严重。通过不杀死细菌，避免了毒素的释放。我的实验室一直在开发和测试新的抗毒性化合物，并研究它们的功能。我们“重新发现”了一种对动物安全的化合物，称为aurodox，实际上是在20世纪70年代早期从土壤中的其他细菌中发现的。当我们使用奥诺多克斯与细菌，导致严重的疾病，特别是臭名昭著的“汉堡虫”“E。大肠杆菌O 157”我们能够关闭细菌用来附着在宿主细胞上的主要武器。实际上，我们只是关闭了用于附着在肠道上的锚，这应该可以确保细菌被简单地冲洗出体外。在这项工作中，我们希望证明，奥诺多克斯可以预防或治疗疾病，并确切地了解它是如何工作的。我们还想看看奥若多克斯是否对我们肠道中的“好”细菌有任何负面影响。解决这些问题将为使用aurodox作为治疗EHEC的第一种方法铺平道路，并且更广泛地表明，抗毒力方法是传统抗生素的可行替代品。

Antibiotics have been used for many years and are central to the treatment of many common bacterial infections. However, because antibiotics kill bacteria, there is a strong selection for mutants, slightly different from the parental type of bacteria, which are not killed: a new resistant form. These resistant cases of bacteria that are no longer susceptible to common antibiotics means that there is a great need for new alternative forms of treatment. Of all the bacteria that causes problems, the gram negative family are the hardest treat because they rapidly develop resistance. One possibility is to render the disease-causing bacteria less dangerous by turning off their offensive weapons. Compounds that "turn off' bacterial weapons are called "anti-virulence" compounds because they don't try to kill the bug, they just render them less dangerous. Imagine taking an army and removing all its key weapons- it's a lot less effective. Using anti-virulence factors is attractive for the following reasons:(1) Anti-virulence compounds "disarm" bacteria rather than killing them, generating less selection for resistant mutants.(2) Secondary infections associated with antibiotic treatment such as those caused by Clostridium difficile and Candida albicans should also be dramatically reduced as natural "good" bacteria are not wiped out during treatment. (3) For toxin-producing bacteria treatment with traditional antibiotics is controversial, with some reports of increased release of toxins and more severe symptoms. By not killing the bacteria, toxin release is avoided.My lab has been developing and testing new anti-virulence compounds and working out how they function. We "re-discovered" a compound that is safe for animals, called aurodox which was actually found in the early 1970s from other bacteria that live in the soil. When we use aurodox with bacteria that cause serious diseases, specifically the infamous "burger bug" "E. coli O157" we are able to switch off the major weapon the bacteria use to attach to host cells. In effect we are just switching off the anchor used to attach to the gut, which should ensure the bacteria are simply flushed out of the body. In this work we want to show that aurodox can prevent or treat disease and also work out exactly how it works. We also want to see if aurodox has any negative effects on the "good" bacteria in our guts. Answering these questions would pave the way to use aurodox as the first treatment against EHEC and, more widely, show that anti-virulence approaches are a viable alternative to traditional antibiotics.