Preliminary study on the antibacterial effect of lactobacillus combined with meropenem on methicillin-resistant Staphylococcus aureus
Compared with ordinary Staphylococcus aureus, infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have longer hospital stays and higher mortality rates. The 2020 CHINET China Bacterial Resistance Surveillance showed that the detection rate of MRSA was relatively high, at 31.0%, among Staphylococcus aureus clinically isolated from medical institutions in major regions of China. Vancomycin and daptomycin are the most commonly used antibiotics for treating MRSA infections in clinical practice, and their monotherapy has been approved as a monotherapy for MRSA bacteremia. There is data showing that the effectiveness of treatment according to this standard is very limited. Severe MRSA infections such as MRSA bacteremia and MRSA infective endocarditis have a high mortality rate, especially MRSA bacteremia, whose mortality rate has been increasing year by year, currently reaching 30%. Compared with beta lactam antibiotics, vancomycin has a relatively slower bactericidal rate, poor tissue permeability, and potential toxicity. Daptomycin has the risk of acute kidney injury, which may be related to treatment failure. In addition, in recent years, strains of vancomycin resistant Staphylococcus aureus and daptomycin resistant strains have also been found on the bed. Therefore, there is an urgent need to search for and develop new drugs and strategies for treating MRSA infections.

NIS is a ribosomal synthetic peptide, a secondary metabolite of bacteria, with broad-spectrum antibacterial activity. It has been widely used as a food preservative worldwide and has been reported to have a synergistic effect on certain antibiotics. MEM is a novel β – lactam antibiotic with advantages such as stability against β – lactam enzymes and fewer adverse reactions, but it is not commonly used for the treatment of Gram positive bacterial infections. This study preliminarily explored the antibacterial effect and potential mechanism of NIS combined with MEM on MRSA, providing a research basis for the development of new antibacterial treatment plans.

NIS is a bacteriocin produced by the genera Lactococcus and Streptococcus. It is a natural peptide compound that can effectively inhibit most Gram positive bacteria that cause food spoilage, especially those that produce spores.

NIS can form permeable pores on bacterial cell membranes and inhibit the synthesis of bacterial cell walls. The antibacterial mechanism of MEM is mainly to inhibit the synthesis of cell walls and not be hydrolyzed by β – lactases produced by bacteria. This study shows that NIS exhibits antibacterial activity when acting alone on MRSA isolates and Staphylococcus aureus standard strain ATCC25923, which is consistent with previous reported research results. In addition, this study also shows the synergistic inhibitory effect of NIS and MEM on MRSA strains, which may be related to NIS’s ability to improve cell membrane permeability.

During anti infection treatment, the concentration of antibiotics in the biofilm of the lesion site decreases as it moves inward. Bacteria located deep inside the biofilm are more likely to develop resistance under the stimulation of low concentrations of antibiotics, which can increase the probability of resistant strains. At the same time, the protection of the biofilm on the bacterial cells makes it difficult for antibiotics to enter, and bacteria in a low metabolic state are less sensitive to antibiotics. This is the main reason why chronic infection lesions are difficult to clear in clinical practice, and the condition is recurrent and persistent. This study found that NIS alone can reduce the amount of biofilm produced by Staphylococcus aureus, while when MEM is combined with NIS alone, the amount of biofilm produced is not significantly reduced compared to NIS alone. This may be due to the fact that biofilm formation is not a random accumulation of bacteria, and the various stages from planktonic state to biofilm formation are influenced by extracellular matrix components, various complex and ordered signaling pathways, and the environment in which they are located. The destruction of MRSA biofilm is mainly caused by NIS, while MEM does not have a synergistic effect.

This study found through an infection model of the model organism, the wax moth, that the combination of NIS and MEM can significantly improve the survival rate of MRSA infected wax moths. This preliminary evidence suggests that NIS and MEM have a significant inhibitory effect on the toxicity of MRSA in vivo. According to the above research, it may be related to the reduction of bacterial survival rate by drug combination. Previous studies have found that the combination of NIS and antibiotics can significantly reduce the production of Staphylococcus aureus enterotoxin (SEC), and the increase in the survival rate of wax moths in this study may also be related to this.

Pathological and toxicological studies have shown that NIS is safe and non-toxic for the human body, therefore it has high application value. This study found that its co use with MEM has a synergistic inhibitory effect on MRSA, and hopes to provide reference for improving treatment plans in clinical practice.