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

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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.