A New Front in the War on Superbugs: Synthetic and Biological Studies on the Potent Antibiotic Anthracimycin

细菌感染正变得越来越难以用现有的抗生素治疗，人们普遍认为需要新的治疗方法。政府和世卫组织继续强调开发新抗生素是一个高度优先的领域。然而，由于抗生素作为最后手段的商业回报率低，制药部门在开发这些抗生素方面处于不利地位。蒽霉素是一种新发现的聚酮化合物，具有很强的革兰氏阳性抗生素活性，特别是对炭疽病原体和MRSA具有活性。值得注意的是，鉴于ESBL的出现，发现由蒽霉素制备的氯化蒽霉素类似物对革兰氏细菌具有活性，并且两种分子均显示通过抑制细菌中DNA/RNA合成的未知作用模式发挥其活性。一种相关的天然产物chlorotonil A也已被报道和合成，但其抗生素活性尚未公开。开发新的抗菌药物作为最后治疗手段的重要性和紧迫性怎么强调都不过分，而炭疽霉素的发现为实现这一目标提供了一个新的、令人兴奋的和及时的机会。该提案将建立在我们之前EPSRC资助的抗MRSA活性天然产物合成领域的工作（EP/F005970）的基础上，并寻求快速响应炭疽霉素的披露，并在开发这些分子作为最后手段的抗生素领域建立领先地位。该项目汇集了天然产物合成和微生物学方面的专家，旨在开发蒽霉素、氯化蒽霉素类似物和百菌清A的化学合成，然后阐明它们发挥抗生素活性的机制。该项目的重点是合成这些分子，并扩大这种新型聚酮化合物对革兰氏菌的作用潜力，使其与医疗保健技术挑战主题，特别是相关的新型治疗和治疗技术提出了“重大挑战”。

Bacterial infections are becoming increasingly hard to treat with current antibiotics and it is well recognised that new treatments are required. The government and the WHO continue to highlight the development of new antibiotics as an area of high priority. However; the pharmaceutical sector is poorly placed to develop these due to the low commercial return on antibiotics of last resort. Anthracimycin is a newly discovered polyketide with potent Gram +ve antibiotic activity, and is especially active against the anthrax pathogen and MRSA. Significantly, given the emergence of ESBLs, the chlorinated anthracimycin analogue, which was prepared from anthracimycin, was found to be active against Gram -ve bacteria, and both molecules were shown to exert their activities via an unknown mode of action which inhibits DNA/RNA synthesis in the bacteria. A related natural product chlorotonil A has also been reported and synthesised but its antibiotic activity has not been disclosed. The importance and urgency of developing new antibacterial agents as treatments of last resort cannot be overstated, and the discovery of anthracimycin provides a new, exciting and timely opportunity to do this. This proposal will build on our previous EPSRC-funded work in the area of the synthesis of natural products active against MRSA (EP/F005970) and seeks to rapidly respond to disclosure of anthracimycin and establish a leading presence in the field of developing these molecules as antibiotics of last resort. This project brings together experts in natural product synthesis and microbiology and aims to develop a chemical synthesis of anthracimycin, chlorinated anthracimycin analogue and chlorotonil A and then elucidate the mechanism by which they exert their antibiotic activity. The project's focus on synthesising these molecules and in expanding the potential of this novel polyketide to function against Gram -ve bacteria aligns it with the healthcare technology challenge theme and especially the associated novel treatment and therapeutic technologies proposed "grand challenge".