Atomically precise, multi-ligand functionalised metal nanoclusters to combat bacterial antibiotic resistance

细菌耐药性(BAR)是“对全球健康的最大威胁之一”。虽然传统的抗生素发现很有价值，但它漫长、昂贵，而且由于细菌对抗生素作用的进化适应，一旦临床使用，快速BAR是不可避免的。而纳米材料可以在一种试剂中提供几种抗菌模式，使细菌更难产生耐药性。一些纳米材料可以恢复抗生素对多重耐药细菌的活力，从而可以提供一种更便宜、更快、更强大的抗生素替代品来应对BAR挑战。尽管取得了很大进展，但大多数研究都集中在提高纳米材料的体外抗菌效力上，很少考虑平移。到目前为止，大多数抗菌纳米材料仍然是混合尺寸的颗粒，没有明确的化学式，并且在体内表现出有限的稳定性、生物相容性和不希望的身体清除。这些都极大地限制了它们在临床翻译中的潜力。我们将通过开发原子精确的、多配体功能化的M25纳米团簇(NCS)来解决这些问题。我们的目标是M25SR18 NC(SR=硫醇配体)，因为它具有高度的稳定性、明确的分子结构和简便的合成方法。我们将通过多功能配基涂层(分别用于抗菌效力、体内稳定性和靶向性)来设计具有良好稳定性、生物相容性和抗菌效力的纳米CS。我们将通过NC的强近红外荧光直接跟踪NC细胞之间的相互作用、细胞内的运输和生物分布。我们将利用细菌培养和有无抗生素的生物膜模型来评估NCS的抗菌性能，以探索潜在的协同作用，并建立表面-结构-功能关系和抗生素NCS的设计规则。

Bacterial antibiotic resistance (BAR) is "one of the biggest threats to global health". While traditional antibiotic discovery is valuable, it is lengthy, expensive, and moreover, rapid BAR is inevitable once in clinical use, due to evolutionary adaptation of bacteria to antibiotic actions. Whereas nanomaterials can offer several antibacterial modes in one agent, making it much harder for bacteria to develop resistance. Some nanomaterials can re-vitalise antibiotics against multidrug resistant bacteria, thus can offer a cheaper, faster and robust alternative to antibiotics to address BAR challenge. Despite great advance, most researches are focused on improving nanomaterials' in vitro antibacterial potencies with little consideration of translation. To date, most antibacterial nanomaterials remain mixed size particles without defined chemical formula, and exhibit limited in vivo stability, biocompatibility and undesirable body clearance. These have greatly limited their potential for clinical translation. We will address such issues by developing atomically precise, multi-ligand functionalised M25 nanoclusters (NCs). We target the M25SR18 NC (SR = thiol ligand) owing to high stability, well-defined molecular structure, and facile synthesis method. We will engineer NCs with excellent stability, biocompatibility and antibacterial potency via multi-functional ligand coating (each for antibacterial potency, in vivo stability & targeting). We will directly track NC-cell interactions, intracellular trafficking and bio-distribution via NC's strong NIR fluorescence. We will evaluate NCs' antibacterial properties using bacteria culture and biofilm models with & without antibiotics to probe potential synergy and establish surface-structure-function relationships and a design rule for antibiotic NCs.