Activating a Silver Lipoate Nanocluster with a Penicillin Backbone Induces a Synergistic Effect against S. aureus Biofilm

Many antibiotic resistances to penicillin have been reported, making them obsolete against multiresistant bacteria. Because penicillins act by inhibiting cell wall production while silver particles disrupt the cell wall directly, a synergetic effect is anticipated when both modes of action are incorporated into a chimera cluster. To test this hypothesis, the lipoate ligands (LA) of a silver cluster (Ag₂₉) of known composition (Ag₂₉LA₁₂)^[3-] were covalently conjugated to 6-aminopenicillanic acid, a molecule with a β-lactam backbone. Indeed, the partially conjugated cluster inhibited an Staphylococcus aureus biofilm, in a dose-response manner, with a half-maximal inhibitory concentration IC₅₀ of 2.3 μM, an improvement over 60 times relative to the unconjugated cluster (IC₅₀ = 140 μM). An enhancement of several orders of magnitude over 6-APA alone (unconjugated) was calculated (IC₅₀ = 10,000 μM). Cell wall damage is documented via scanning electron microscopy. A synergistic effect of the conjugate was calculated by the combination index method described by Chou-Talalay. This hybrid nanoantibiotic opens a new front against multidrug-resistant pathogens.