Synthesis and Analysis of Copper-Loaded Micelles to Address Antimicrobial Resistance

碳青霉烯类是一种广谱b-内酰胺类药物，用作最后的抗生素。令人担忧的是，碳青霉烯耐药性正在出现，导致细菌感染死亡人数增加。金属-b-内酰胺酶（MBL）酶与碳青霉烯抗性有关。抑制MBL酶可以关闭抗生素耐药性，我们一直在研究铜吡硫酮配合物作为MBL酶的抑制剂。这些复合物是有活性的，但被细菌细胞吸收是一个限制因素。以前，我们已经改变了吡硫酮配体，试图增加摄取，并取得了一些成功。在这个项目中，我们将使用聚合物胶束来提高铜的吸收率。本项目的目的是生产装载有mbl抑制剂铜-吡硫酮配合物的胶束。这将涉及到吡硫酮配体、它们的铜配合物和聚合物胶束前体的化学合成。胶束将用动态光散射表征，铜配合物的加载和释放将被量化。接下来，将进行生物测定，以评估铜的摄取（ICP-MS）和MBL在细菌内的抑制程度。除了这个最初的目标之外，我们希望开发出针对细菌选择性的胶束，并生产出将铜复合物与碳青霉烯类抗生素结合在一起的胶束——一种同时递送碳青霉烯类抗生素并抑制耐药机制的一体化胶束。

Carbapenems are broad-spectrum b-lactams used as last-resort antibiotics. Worryingly, carbapenem-resistance is emerging, leading to increased deaths from bacterial infection. Metallo-b-lactamase (MBL) enzymes are linked to carbapenem-resistance. Inhibition of MBLs switches off antibiotic resistance and we have been studying copper pyrithione complexes as inhibitors of the MBL enzymes. These complexes are active, but uptake into the bacterial cell is a limiting factor. Previously, we have varied the pyrithione ligand in an attempt to increase uptake with some success. In this project, we will use polymeric micelles to improve uptake of the copper. The aim of this project is to produce micelles loaded with the MBL-inhibitor copper- pyrithione complexes. This will involve chemical synthesis of pyrithione ligands, their copper complexes and polymer micelle precursors. Micelles will be characterized using dynamic light scattering and copper complex loading and release will be quantified. Next, biological assays will be carried out to assess the copper uptake (ICP-MS) and the extent of MBL inhibition within the bacteria. Beyond this initial aim, we hope to develop micelles that target the bacteria selectivity and to produce micelles that combine the copper complex with the carbapenem antibiotic - an all-in-one micelle that simultaneously delivers carbapenem antibiotic and inhibits the resistance mechanism.