Assessing the Potential of Gallic Acid and Methyl Gallate to Enhance the Efficacy of β-Lactam Antibiotics against Methicillin-Resistant Staphylococcus aureus by Targeting β-Lactamase: In Silico and In Vitro Studies

Methicillin-resistant Staphylococcus aureus (MRSA), a global health concern, has prompted research into antibiotic adjuvants as a potential solution. Although our group previously reported the enhancing effects of gallic acid (GA) and methyl gallate (MG) on penicillin G activity against MRSA, the synergistic potential with other beta-lactam antibiotics and the underlying mechanism have not been fully explored. Therefore, this study primarily aimed to investigate the antibacterial synergism with beta-lactam antibiotics through disc diffusion, checkerboard, and time-kill assays. The beta-lactamase inhibition was also examined through both molecular modeling and in vitro experiments. Additionally, bacterial morphology changes were studied using a scanning electron microscopy (SEM). The results revealed that both GA and MG exhibited anti-MRSA activity and showed indifferent effects when combined with beta-lactam antibiotics against methicillin susceptible S. aureus (MSSA). Interestingly, MG demonstrated synergism with only the beta-lactamase-unstable antibiotics against MRSA with the lowest fractional inhibitory concentration (FIC) indexes of <= 3.75. However, GA and MG exhibited weak beta-lactamase inhibition. Furthermore, GA, MG, and the combination with ampicillin induced the morphological changes in MRSA, suggesting a possible mechanism affecting the cell membrane. These findings suggest that MG could potentially serve as an adjunct to beta-lactam antibiotics to combat MRSA infections.