Development of antimicrobial peptides against Gram-negative antibiotic resistant pathogens

抗生素的使用不足和过度使用导致革兰氏阴性菌对已知抗生素产生耐药性。虽然这是一个全球性问题，但缺乏新的抗生素和替代疗法令人担忧，特别是在SA，免疫系统较弱的患者，如艾滋病毒感染者，极易感染。革兰氏阴性菌感染的诊断通常很困难，特别是当这些感染发生在身体深处时。对用于治疗这些感染的抗生素的耐药性使情况变得更糟，因为感染进展未被发现，因此迫切需要新的抗生素和监测治疗成功的新方法。这是一个全球性的危机，只有通过国际科学合作，才能发现新的抗生素。这一进程的一个重要方面是建立基于肽的抗生素药物发现的能力。这种努力的一个重点是为南非历史上处于不利地位的背景和机构的科学家提供成为这一研究领域领导者的机会。通过这一过程，下一代科学家的培训对于确保继续成功找到新的方法来对抗不断演变的细菌感染的永久威胁至关重要，特别是在南非独特的医疗保健挑战的背景下。其中一种方法是基于使用抗菌肽（AMP），这是自然界自己的抗生素，在整个进化史中一直有效，但尚未突破临床应用。AMP是包括人类在内的各种生物体的先天免疫系统的关键组成部分，并且具有根除感染的能力。现在，为了证明AMP可以被开发为用于患者治疗的抗生素，我们将学习如何修饰它们以增加它们的安全性和稳定性。我们还将通过在与患者感染环境更密切匹配的条件下进行测试，确保它们更有可能在患者身上发挥作用。现有的实验室抗生素测试方法是有缺陷的，因为它们经常低估或高估不同类型抗生素的效力，最明显的是AMP。除了治疗患者外，我们还希望使用AMP来监测他们的恢复情况，或者告诉我们何时应该使用其他抗生素。我们将采用最近开发的成像技术来研究大脑活动或发现肿瘤，并揭示放射治疗和/或化疗的成功。AMP可以被修改为携带放射性示踪剂，并在导向引起感染的细菌之前在体内循环。所附的示踪剂用于正电子发射断层扫描（PET）或单光子发射计算机断层扫描（SPECT），其中发射相对低且因此安全的伽马射线剂量。PET或SPECT信号的强度和位置可以在体内以三维方式进行映射，以给出任何感染的位置和程度，并在例如局部感染开始在身体周围扩散时发出信号。由于AMP选择性地靶向细菌，放射性标记可以提供一种快速、非侵入性的感染成像方法，并通过正确的抗生素治疗，快速恢复患者，降低抗生素耐药性发展的风险。通过Newton的资助，英国和南非将建立合作，以加速新的AMP抗生素的创新发现。通过增加来自UP，NWU和SMU的英国和SA研究人员的流动性和交流，两国研究人员之间的联系将得到加强，并将发展新的伙伴关系，可能建立全球竞争前药物发现联盟。这一进程还有一个好处，那就是加强了英国和南非之间的战略关系。

The underuse and overuse of antibiotics has resulted in Gram-negative bacteria becoming resistant to known antibiotics. Although this is a global problem, the lack of new antibiotics and alternative therapy is of concern especially in SA, where patients with a weakened immune system, such as those with HIV, are highly susceptible to infection. The diagnosis of Gram-negative infections is often difficult, especially when these occur deep in the body. The resistance to antibiotics used to treat these infections makes the situation worse as the infection progresses undetected and so both new antibiotics and new ways of monitoring the success of treatment are urgently needed. This is a global crisis and only through an international collaborative scientific effort, will new antibiotics be discovered. An important aspect of this process is to build capacity in peptide based antibiotic drug discovery. A focus of such an endeavour is to provide scientists from historically disadvantaged backgrounds and institutions in SA the opportunity to be leaders in this field of research. Through this process, the training of the next generation of scientists is essential to ensure a continued success to find novel approaches to combat the perpetual threat of evolving bacterial infections, especially in the context of unique health care challenges in South Africa. One such approach is based on using antimicrobial peptides (AMPs), nature's own antibiotics which have remained effective throughout evolutionary history, but which have yet to make a breakthrough into clinical use. AMPs are key components of the innate immune system of a huge variety of living organisms, including humans, and have the ability to eradicate infection. Now, to show that AMPs can be developed as antibiotics for therapeutic application in patients we will learn how to modify them to increase their safety and stability. We will also ensure that they are more likely to work in patient by testing them in conditions that match more closely the patient infection setting. Existing methods of laboratory antibiotic testing are deficient as they often under- or over-estimate the potency of different types of antibiotic, most notably AMPs . As well as treating patients, we want to use AMPs to monitor their recovery or tell us when other antibiotics should be given. We will adapt imaging techniques, recently developed to study brain activity or find tumours and reveal the success of radio- and/or chemo-therapy. AMPs can be modified to carry a radioactive tracer and will circulate around the body before homing in on the bacteria causing infection. The tracer that is attached is used for either positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) where a relatively low, and hence safe, dose of gamma rays is emitted. The intensity and location of the PET or SPECT signal can be mapped in the body in three dimensions to give the location and extent of any infection and to signal when, e.g. a localised infection starts to spread around the body. Since AMPs selectively target bacteria radiolabeling can provide a rapid, noninvasive method for infection imaging and with the correct antibiotic treatment, rapid patient recovery with reduced risk of antibiotic resistance development. Through Newton funding a UK and SA collaboration will be established to accelerate the innovative discovery of new AMP-based antibiotics. Through increased mobility and exchange of UK and SA researchers from UP, NWU and SMU, links between researchers in both countries will be strengthened and new partnerships will be developed with the possible establishment of a global pre-competitive drug discovery consortium. This process has a further benefit and that is the strengthening of the strategic relationship between the UK and South Africa.