Bacterial actin MreB as a new antibiotic target.

Actin homolog MreB plays a crucial role in the synthesis of the bacterial cell wall. Disruption of the MreB filament network results in the disruption of the cell wall, which thus serves an unconventional antibacterial strategy. A22, a small inhibitor molecule, binds directly to the MreB filament, altering its structure and causing a morphological change of the cell, leading to cell death. This effective antibacterial property is shadowed by the fact that at high concentration, A22 is toxic to eukaryotic host cells, so it cannot be administered at higher doses. Vancomycin is a widely used antibiotic targeting Gram-positive bacteria at concentrations as high as 10-20 μg/mL, which can occasionally cause serious side effects. In this study, we present our recent findings that a synergistic interaction exists between A22 and vancomycin, which results in the inhibition of cell proliferation by the combined use of very low concentrations of A22 (6.25 μg/mL) and vancomycin (1.56 μg/mL). In addition, in the presence of A22, vancomycin is effective not only against Gram-positive bacteria but also against Gram-negative bacteria. Since 5 of the 7 most common antibiotic-resistant bacteria according to the WHO are Gram-negative, this synergism between A22 and vancomycin opens a new way of combating bacterial infections. Our spectroscopic results indicate that vancomycin binds directly to MreB; using a computer docking method, we determined the possible binding site of vancomycin on the MreB filament. This newly identified interaction between vancomycin and A22 highlights the potential of the combined use, providing a new strategy to tackle antibiotic resistance.