Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a superbacterium, and when it forms biofilms, it is difficult to treat even with the first-line of antibiotic linezolid (LNZ). Reyanning mixture (RYN), a compound-based Chinese medicine formula, has been found to have inhibitory effects on biofilms. This study aims to explore the synergistic inhibitory effect and corresponding mechanisms of their (LNZ&RYN) combination on the planktonic as well as biofilm cells of MRSA. Broth microdilution and chessboard methods were employed for the determination of minimum inhibitory concentrations (MICs) and synergistic concentration of LNZ&RYN, respectively. The effect of the combined medication on biofilm and mature biofilm of MRSA were observed by biofilm morphology and permeability experiments, respectively. To unveil the molecular mechanism of action of the synergistic combination of LNZ and RYN, RT-PCR based biofilm-related gene expression analysis and ultra-high pressure liquid chromatography-time-of-flight mass spectrometry based endogenous metabonomic analysis were deployed. The results indicated that 1/16RYN as the best combined dose reduced LNZ (4 μg/ml) to 2 μg/ml. The combined treatment inhibited living MRSA before and after biofilm formation, removed the residual structure of dead bacteria in MRSA biofilms and affected the shape and size of bacteria, resulting in the improvement of biofilm permeability. The mechanism was that biofilm-related genes such as agrC, atlA, and sarA, as well as amino acid uptake associated with the metabolism of 3-dehydrocarnitine, kynurenine, L-leucine, L-lysine and sebacic acid were inhibited. This study provides evidence for the treatment of MRSA and its biofilms with LNZ combined with RYN.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is commonly known as a “superbug”, and its infection leads to many refractory diseases such as pneumonia, bacteraemia, and skin and soft tissue infections (Patel, 2009)
Viable bacteria in MRSA biofilms were inhibited in the positive drug LNZ group, but the inhibitory effect was not as good as that the in 1/8RYN group and 1/16RYN group
It is suggested that both Reyanning mixture (RYN) and LNZ can destroy the structure of MRSA biofilm and infiltrate into the biofilm to kill the deep bacteria in the biofilm, but the effect of LNZ is weaker than that of high and middle dose of RYN
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is commonly known as a “superbug”, and its infection leads to many refractory diseases such as pneumonia, bacteraemia, and skin and soft tissue infections (Patel, 2009). MRSA is difficult to treat, and when it forms a mature biofilm, its treatment will be more difficult. The formation of biofilms is considered a way for microorganisms to adapt to harsh environments. The resistance of mature biofilm bacteria to antibiotics and host immune defence is significantly improved and even antibiotics up to 100–1000 times the minimum inhibitory concentration (MIC) cannot kill bacteria in biofilms (David, 2003). Biofilms are one of the important reasons for MRSA resistance. More than 80% of bacterial infections are biofilm-mediated (Stella et al, 2021). How to destroy the structure of biofilms and effectively treat the related infections caused by MRSA and its biofilms has become a hotspot of scientific research
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