The cell envelope of bacteria as a target for chelant and antibiotic combinations

细菌的细胞被膜作为螯合剂和抗生素组合的靶标

• 批准号: 2570178
• 金额: --
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2570178
• 关键词: cell; envelope; bacteria; target; chelant

Bacterial metal and antibiotic resistance are increasingly recognised as processes that evolve in parallel. Although not well-characterised, co-resistance is frequently associated with cellular import and export mechanisms. Indeed, some antibiotics are actively transported to their intracellular targets as metal complexes. Hence disrupting the uptake of both metals and antibiotics, either separately or together, offers significant potential to combat increasingly drug-resistant pathogens. This project emerges from successful efforts, in partnership with Procter & Gamble, to deprive bacterial pathogens of essential metals using metal chelants with differing selectivities. To help determine the mode of action of two chelants with affinities for different metallic species, we isolated chelant-resistant mutants of two bacterial species and identified chromosomal changes from the resulting strains. Several mutations were found that affected the anticipated metal uptake systems. However, additional mutations were identified that altered cell surface molecules, membrane-bound transporters and enzymes engaged in peptidoglycan metabolism. Interestingly, improved resistance to certain antibiotics was also evident in several of the mutants. Moreover, treating bacteria with combinations of chelants and antibiotics identified synergistic, additive and indifferent effects. The wild-type and mutant derivatives of these bacteria therefore provide an excellent opportunity to probe the relationship between antibiotics, metal chelation and cell envelope integrity. This project aims to understand how chelants and antibiotics target and traverse the bacterial envelope and explore links with metal uptake and tolerance. There are significant prospects commercially for improving product formulations through a better understanding of how chelants inhibit bacterial growth. Furthermore, it offers the potential to revitalise existing antibiotics for topical applications in the treatment of wounds, in both medical and veterinary contexts, caused by important antibiotic-resistant pathogens.

细菌的金属和抗生素耐药性越来越被认为是平行进化的过程。虽然没有很好地表征，但共耐药通常与细胞输入和输出机制相关。事实上，一些抗生素作为金属络合物被主动转运到其细胞内靶标。因此，破坏金属和抗生素的吸收，无论是单独还是一起，都为对抗日益耐药的病原体提供了巨大的潜力。该项目源于与宝洁公司合作的成功努力，使用具有不同选择性的金属螯合剂剥夺细菌病原体的必需金属。为了帮助确定两种螯合剂与不同金属物种的亲和力的作用模式，我们分离了两种细菌物种的螯合剂抗性突变体，并从所得菌株中鉴定了染色体变化。发现了几个突变，影响了预期的金属吸收系统。然而，发现了其他突变，这些突变改变了细胞表面分子、膜结合转运蛋白和参与肽聚糖代谢的酶。有趣的是，对某些抗生素的抗性改善在几个突变体中也很明显。此外，用螯合剂和抗生素的组合治疗细菌发现了协同作用、相加作用和无关作用。因此，这些细菌的野生型和突变衍生物提供了一个很好的机会，以探测抗生素，金属螯合和细胞包膜完整性之间的关系。该项目旨在了解螯合剂和抗生素如何靶向和穿过细菌包膜，并探索与金属吸收和耐受性的联系。通过更好地理解螯合剂如何抑制细菌生长来改进产品配方在商业上具有重大的前景。此外，它提供了振兴现有抗生素的潜力，用于在医疗和兽医背景下治疗由重要的耐药性病原体引起的伤口的局部应用。