Modification of vancomycin to overcome bacterial resistance

虽然有许多药物可用于治疗细菌感染，但只有少数化合物能够作为严重感染的最后手段。此外，由于易受药物攻击的细胞靶点数量有限，无休止的追逐：耐药性导致的药物损失和新化合物的开发导致必需化合物池的耗尽。大多数已被完善为目标的药物都源于永恒的自然进化。当出现多重耐药的微生物菌株时，这一池的持续枯竭是有效抗生素失效的主要原因。因此，抗生素开发的关键原则应该是优化调味化合物，通过多种机制攻击细菌和/或加强作用方式来打破耐药性的发展。万古霉素是治疗革兰氏阳性菌引起的多重耐药感染的关键抗生素。不幸的是，万古霉素耐药细菌已经成为医院感染的一个越来越难以治疗的原因。为了获得能够克服万古霉素耐药的万古霉素衍生物，人们已经通过在万古霉素的四个不同位置连接特定的聚阳离子多肽来合成各种衍生物，并研究了它们的体外抗菌活性，展示了通过打破万古霉素耐药的主要类型(Vana、vanB、vanC)对不同的万古霉素耐药肠球菌的潜在作用。在粪肠球菌ATCC51559上，当前的先导化合物(FU002)显示摩尔MIC降低1926倍。这种高的体外效率已经在体内得到证实：在治疗性脓毒症小鼠模型中，FU002显示出显著的CFU减少。此外，新的结合物可能提供高效益，因为它们的体外细胞毒性低，在几个细胞系(肾脏、肝脏、血液)中的细胞毒性测试证明。万古霉素的肾毒性限制了其治疗潜力。基于这些有希望的初步结果，本项目将合成一个万古霉素修饰化合物的文库，并通过各种体外和体内测试(如MIC、细胞毒性、药代动力学、生物分布研究)对其进行表征。为此，Ohlsen实验室应建立肠球菌-小鼠模型，以证明对万古霉素耐药细菌的治疗效率。此外，应研究可能的抗药性机制(发展和诱导)，同时对新型万古霉素修饰的衍生物的作用模式进行评估。由于他们的实验室设备以及Mier和Ohlsen实验室独特的协同专业知识，这两个工作组都是该项目的理想合作伙伴。

While there are numerous drugs available for the therapy of bacterial infections, there is only a few of compounds capable to serve as last resort for severe infections. Moreover, as the number of cellular targets vulnerable by drugs is limited, the endless chase: loss of drugs caused by resistance and the development of novel compounds results in the exhaustion of the pool of essential compounds. Most of the drugs that have been perfected to a target originate from eternal natural evolution. The continuous depletion of this pool is the main reason why efficacious antibiotics fail upon occurrence of multiresistant microbial strains. Consequently, the key principle of antibiotics development should be the optimization of the seasoned compounds to break development of resistance either by attacking bacteria using multiple mechanisms and/or reinforcement of the mode of action.Vancomycin is the pivotal antibiotic for the treatment of multi-drug resistant infections caused by Gram-positive bacteria. Unfortunately, vancomycin-resistant bacteria have become an increasingly difficult-to-treat cause of nosocomial infections. In order to obtain vancomycin derivatives that are able to overcome vancomycin resistance, a variety of derivatives have already been synthesized by the conjugation of specific polycationic peptides at four different sites of vancomycin and studied with respect to their in vitro antimicrobial activity, demonstrating the potential by breaking the main types of vancomycin resistance (vanA, vanB, vanC) on different vancomycin-resistant enterococci. On an E. faecium ATCC51559, the current lead compound (FU002) showed a 1926-fold reduced molar MIC. This high in vitro efficiency could already be confirmed in vivo: FU002 showed significant reduction of the CFU in a therapeutic sepsis-mouse-model.Furthermore, the novel conjugates may offer high benefit due to their low in vitro cytotoxicity as proven by cytotoxicity assays in several cell lines (kidney, liver, blood). The therapeutic potential of vancomycin is limited by its nephrotoxicity. In contrast, the novel compounds do not show accumulation in the kidneys and might be designed to allow higher target to non-target ratios.Based on these promising first results, in this project a library of vancomycin-modified compounds shall be synthesized and characterized by a variety of in vitro and in vivo tests (e.g. MIC, cytotoxicity, pharmacokinetics, biodistribution studies). For this purpose an enterococci- mouse model shall be established by the Ohlsen lab in order to demonstrate the efficiency of treatment of vancomycin resistant bacteria. Additionally, possible resistance mechanisms (development and induction) shall be investigated accompanied by the evaluation of the mode of action of the novel vancomycin-modified derivatives. Due to their lab equipment and the unique synergistic expertise of the Mier and Ohlsen lab, both working groups represent ideal partners for this project.