Unraveling Multicopper [Cu] and [Cu] Clusters with Rare μ-Sulfato and Linear μ-Oxido-Bridges As Potent Antibiofilm Agents Against Multidrug-Resistant

In this research article, two multicopper [Cu] and [Cu] clusters, [Cu(cpdp)(μ-SO)(Cl)(HO)]·3HO () and [Cu(cpdp)(μ-O)(Cl)(HO)]·2Cl () (Hcpdp = ,'-bis[2-carboxybenzomethyl]-,'-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol), have been explored as potent antibacterial and antibiofilm agents. Their molecular structures have been determined by a single-crystal X-ray diffraction study, and the compositions have been established by thermal and elemental analyses, including electrospray ionization mass spectrometry. Structural analysis shows that the metallic core of is composed of a trinuclear [Cu] assembly encapsulating a μSO group, whereas the structure of represents a hexanuclear [Cu] assembly in which two trinuclear [Cu] motifs are exclusively bridged by a linear μO group. The most striking feature of the structure of is the occurrence of an unusual linear oxido-bridge, with the Cu3-O6-Cu3' bridging angle being 180.00°. Whereas can be viewed as an example of a copper(II)-based compound displaying a rare μ:η:η:η bridging mode of the SO group, is the first example of any copper(II)-based compound showing an unsupported linear Cu-O-Cu oxido-bridge. Employing variable-temperature SQUID magnetometry, the magnetic susceptibility data were measured and analyzed exemplarily for in the temperature range of 2-300 K, revealing the occurrence of antiferromagnetic interactions among the paramagnetic copper centers. Both and exhibited potent antibacterial and antibiofilm activities against methicillin-resistant (MRSA BAA1717) and the clinically isolated culture of methicillin-resistant (MRSA CI1). The mechanism of antibacterial and antibiofilm activities of these multicopper clusters was investigated by analyzing and determining the intracellular reactive oxygen species (ROS) generation, lipid peroxidation, microscopic observation of cell membrane disruption, membrane potential, and leakage of cellular components. Additionally, and showed a synergistic effect with commercially available antibiotics such as vancomycin with enhanced antibacterial activity. However, possesses higher antibacterial, antibiofilm, and antivirulence actions, making it a potent therapeutic agent against both MRSA BAA1717 and MRSA CI1 strains.