Enhancing the Susceptibility of Methicillin‐Resistant Staphylococcus aureus to β‐Lactam Antibiotics Through the Use of 4‐Methoxysalicyl Aldehyde

The rise of β-lactamase-producing bacteria remains a significant public health threat. Their rapid proliferation across various environments has led to a marked decline in the clinical effectiveness of β-lactam antibiotics against these resistant strains. Targeting β-lactamase activity offers a promising approach to managing resistant bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA). Studies on in vitro MIC killing curves, β-lactamase activity assays, and quantitative real-time PCR of related β-lactamase genes demonstrate that 4-methoxy salicyl aldehyde (HMB) unveiled its ability to significantly boost the potency of various β-lactam antibiotics against the S. aureus USA300 strain. Additionally, the study provided compelling evidence that HMB not only inhibits β-lactamase activity but also amplifies the intracellular accumulation of reactive oxygen species within MRSA, thereby contributing to its heightened susceptibility to these antibiotics. It concurrently impacted both biofilm formation and the expression of related genes in MRSA. This dual mechanism of action underscores HMB's potential as a valuable adjunct in the treatment of β-lactamase-producing resistant bacteria. The combination of HMB and cefixime effectively protected host cells from MRSA-induced damage in a co-culture system. In vivo experiments confirmed that the synergistic treatment effectively controlled S. aureus infections, which therapeutic strategy increased survival rates, reduced bacterial colonization, inflammation, and tissue damage in the pneumonia mouse model. Additionally, HMB significantly accelerated skin wound healing in those infected with S. aureus USA300. These findings identify HMB as a novel β-lactamase inhibitor with the potential to combat β-lactamase-producing bacteria.