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

[Image: see text] 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 (Ag(29)) of known composition (Ag(29)LA(12))([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 IC(50) of 2.3 μM, an improvement over 60 times relative to the unconjugated cluster (IC(50) = 140 μM). An enhancement of several orders of magnitude over 6-APA alone (unconjugated) was calculated (IC(50) = 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.