Extending bicyclomycin treatment of multi-drug resistant Gram-negative pathogens

抗生素从传染病中拯救了数百万人的生命，可以说是20世纪最伟大的医学发现。不幸的是，21世纪对公共健康的最大威胁之一是耐多药细菌感染的增加。这一上升是由于医药和农业中抗生素的不当使用以及新型抗生素发现的短缺造成的。这促使世界卫生组织(WHO)警告称，“随着新抗生素上市的匮乏，采取行动以避免不断发展的全球医疗保健危机的必要性日益迫切”，英国首席医疗官萨莉·戴维斯爵士(Dame Sally Davies)宣布，“我们开发新药的速度也不够快”。这是一个全球问题，需要采取全球行动，特别是在治疗耐多药的革兰氏阴性细菌感染方面。革兰氏阴性菌对临床上使用的许多抗生素都有天然的抗药性，经过多年的治疗，已经对大多数其他抗生素产生了抗药性。有各种方法来解决这个日益严重的问题，包括重新利用“旧的”抗生素。这些药物在人体临床试验中经过了彻底的有效性和安全性测试，但由于各种原因，当时并未广泛使用。例如，当时可能已经有了更好的广谱替代品。多重抗药性的上升意味着这些分子现在可能非常有用，特别是因为它们缺乏临床使用意味着致病细菌还没有机会产生抗药性。此外，新的实验有时可以揭示出早期研究中没有确定的抗菌活性。双环素就是这种情况，这是一种古老的抗生素，以前被证明对革兰氏阴性菌有中等的抑菌活性。“抑菌”是指抗生素会阻止细菌生长，但不会主动杀死细菌，这可能会导致感染的持久性。令人兴奋的是，最近的研究表明，当双环素与另一种抑菌抗生素一起使用时，它实际上可以杀死细菌(杀菌)。这种意想不到的活性使双环霉素成为一种非常有希望的抗生素，当与另一种药物联合使用时，它将用于治疗革兰氏阴性细菌感染。因此，我们建议开展进一步的工作，以确定双环素是否可以在临床上广泛使用。这将包括为这种新的活性测试更准确的感染模型，并确定可以与双环素一起使用以阻止耐药性发展的新化合物。双环素是一种由非致病土壤细菌自然产生的分子。像这样的天然产品是由一系列酶(蛋白质)的作用产生的，这些酶(蛋白质)由细菌基因组中的基因(DNA)编码。因此，我们的目标是发现负责双环素生产的基因。这一发现将使我们能够对该途径进行修改，以制造更多的化合物，这将使其能够在感染模型中进行研究。我们还可以修改该途径来产生新版本的双环素，它可能比原来的化合物具有更好的活性，或者克服抗性机制。

Antibiotics have saved millions of lives from infectious diseases and are arguably the greatest medical discovery of the 20th century. Unfortunately, one of the biggest threats to public health in the 21st century is the rise of multi-drug resistant bacterial infections. This rise has been caused by the improper use of antibiotics in medicine and agriculture combined with a shortage in the discovery of new types of antibiotics. This has prompted the World Health Organisation to warn that "with a dearth of new antibiotics coming to market, the need for action to avert a developing global crisis in health care is increasingly urgent", and the UK's Chief Medical Officer, Prof. Dame Sally Davies, to declare that "we are also not developing new drugs fast enough". This is a global problem that requires global action, particularly for the treatment of multi-drug resistant Gram-negative bacterial infections. Gram-negative bacteria are naturally resistant to many antibiotics used clinically, and have evolved to be resistant towards most other antibiotics following years of treatment with those medicines. There are various approaches to tackle this growing problem, including re-purposing "old" antibiotics. These are drugs that were thoroughly tested for efficacy and safety in human clinical trials, but were not then widely used for a variety of reasons. For example, better broad-spectrum alternatives may have been available at the time. The rise of multi-drug resistance means that these molecules may now be very useful, especially because their lack of clinical use means that there has not been an opportunity for resistance to develop in disease-causing bacteria. Additionally, new experiments can sometimes reveal antibacterial activities that were not identified in earlier research. This is the case for bicyclomycin, an old antibiotic that had previously been shown to have moderate bacteriostatic activity towards Gram-negative bacteria. "Bacteriostatic" means that the antibiotic stops bacterial growth, but does not actively kill the bacteria, which can lead to the persistence of an infection. Excitingly, recent work has shown that bicyclomycin can actually kill bacteria ("bactericidal") when it is used alongside another bacteriostatic antibiotic. This unexpected activity makes bicyclomycin a highly promising antibiotic for the treatment of Gram-negative bacterial infections when used in combination with another drug. Therefore, we propose to carry out further work to determine whether bicyclomycin can be widely used in the clinic. This will include testing more accurate models of infection for this novel activity and identifying new compounds that can be used alongside bicyclomycin to stop resistance developing. Bicyclomycin is a molecule that is made naturally by non-pathogenic soil bacteria. Natural products such as this are produced by the action of a series of enzymes (proteins), which are encoded by genes (DNA) in the bacterial genome. Thus, we aim to discover the genes that are responsible for bicyclomycin production. This discovery will allow us to make modifications to the pathway to make more of the compound, which will enable its study in infection models. We can also modify the pathway to produce new versions of bicyclomycin, which might have better activity than the original compound or overcome resistance mechanisms.