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

超级细菌战争的新战线：强效抗生素蒽霉素的合成和生物学研究

• 批准号: EP/M008401/1
• 负责人: Paul Clarke
• 金额: $ 76.33万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM008401%2F1
• 关键词: New; Front; War; Superbugs; Synthetic

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".

细菌感染越来越难以治疗目前的抗生素治疗，人们认识到需要新的治疗方法。政府和谁继续强调新抗生素的发展是一个优先级的领域。然而;由于最后的度假村的抗生素回报率较低，因此在制定这些部门的情况下，制造这些领域的位置不佳。炭疽霉素是一种具有有效的革兰氏 +VE抗生素活性的新发现的聚酮化合物，对炭疽病原体和MRSA特别有效。值得注意的是，鉴于ESBL的出现，发现氯霉素类似物是由炭疽霉素制备的，发现对GRAM -VE细菌具有活性，并且两个分子都显示出通过抑制细菌中DNA/RNA合成的未知作用模式发挥其活性。还报道并合成了相关的天然产物叶绿素A，但尚未披露其抗生素活性。发展新的抗菌剂作为最后一种治疗方法的重要性和紧迫性不可夸大，而炭疽菌素的发现为此提供了一个新的，令人兴奋和及时的机会来做到这一点。该提案将建立在我们以前由EPSRC资助的工作中，在综合自然产品的领域，对MRSA（EP/F005970）进行了活跃的天然产品，并试图快速响应炭疽菌素的披露，并在开发这些分子的领域中建立了领先的存在，以此作为抗生素的抗生素。该项目汇集了天然产物合成和微生物学专家，旨在开发炭疽霉素，氯化蒽霉素类似物和氯托尼A的化学合成，然后阐明它们发挥抗生素活性的机制。该项目的重点是综合这些分子，并扩大这种新型聚酮化合物对GRAM -VE细菌起作用的潜力，使其与医疗保健技术挑战主题，尤其是相关的新颖治疗和治疗技术“大挑战”一致。