Aversion Therapy for Bacteria: Repurposing Aurodox

抗生素已经使用多年，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，这些突变体与未被杀死的亲本类型细菌略有不同：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，革兰氏阴性家族是最难治疗的，因为它们会迅速产生耐药性。一种可能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”化合物，因为它们不试图杀死细菌，只是降低它们的危险性。想象一下，拿走一支军队的所有关键武器，效果会小得多。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，减少了抗性突变体的选择。(2)与抗生素治疗相关的继发感染，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”细菌在治疗期间不会被消灭。(3)对产毒菌使用传统抗生素治疗存在争议，有报道称毒素释放增加，症状加重。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，称为氧化还原，实际上是在20世纪70年代初从生活在土壤中的其他细菌中发现的。当我们将氧化还原用于导致严重疾病的细菌，特别是臭名昭著的“汉堡虫”“大肠杆菌O157”时，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，我们只是关闭了附着在肠道上的锚点，而肠道本应确保细菌被简单地排出体外。在这项工作中，我们想要证明氧化还原可以预防或治疗疾病，并找出它的确切工作原理。我们还想看看氧化还原是否对我们肠道中的“好”细菌有任何负面影响。回答这些问题将为使用氧化还原作为治疗肠出血性大肠杆菌的第一种方法铺平道路，并且更广泛地表明抗毒方法是传统抗生素的可行替代方法。

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.