Advancements in MRSA treatment: the role of berberine in enhancing antibiotic therapy

Abstract

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a significant public health problem. This study investigated the antimicrobial properties and mechanisms of berberine (BBR), a plant alkaloid, against MRSA, evaluating its potential to enhance antibiotic therapy.

Results: Berberine only demonstrated variable but significant inhibitory effects on 50 clinical MRSA strains. When combined with antibiotics, synergistic effects were observed only with amikacin in 6 of the 50 MRSA strains. BBR disrupted MRSA cell wall integrity, leading to leakage of cellular contents. Network pharmacology analysis revealed that BBR targets multiple pathways essential for bacterial survival.

Conclusion: The study confirmed the potent antimicrobial activity of berberine against MRSA and its capability to act synergistically with traditional antibiotics. Berberine's impact on cell wall integrity and bacterial survival pathways highlights its potential as an adjunct therapy in MRSA treatment.

Keywords: Berberine; Cell wall damage; Methicillin-resistant Staphylococcus aureus; Minimum inhibitory concentration; Network pharmacology.

Fig. 1

Susceptibility test results of 50 MRSA strains against 12 antibiotics. Note: Red indicates resistance (R: Resistance), yellow indicates intermediate sensitivity (I: Intermediary), and blue indicates sensitivity (S: Sensitivity). Most MRSA strains exhibited high sensitivity to vancomycin and linezolid while showing near-complete resistance to penicillin G

Fig. 2

Bar graphs illustrating the effects of different concentrations of BBR on the proliferation of MRC-5 and FHC cells. Note: (A) The effect of different concentrations of BBR on the proliferation of MRC-5 cells. (B) The effect of different concentrations of BBR on the proliferation of FHC cells. Below a concentration of 64 µg/mL, BBR did not cause a significant impact on cell proliferation. (Compared to the control group, ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05; ns: not statistically significant)

Fig. 3

Time-kill curves of MRSA2022 treated with different concentrations of BBR in combination with three antibiotics. Note: (A) The antibacterial effect of BBR in combination with GEN on MRSA2022. (B) The antibacterial effect of BBR in combination with LEV on MRSA02. (C) The antibacterial effect of BBR in combination with AMI on MRSA2022

Fig. 4

Study on the impact of BBR on the permeability and viability of MRSA cell membranes. Note: (A) Illustrates the effect of different concentrations of BBR on the conductivity of the culture medium for the MRSA2202 strain, reflecting the disruption of bacterial cell membrane integrity. (B) Flow cytometry analysis demonstrates the percentage of live and dead bacteria in the USA300 strain after treatment with BBR, highlighting its bactericidal efficacy

Fig. 5

TEM observation of the MRSA2202 strain cell wall at 80,000x magnification. Note: (A) Low concentration (8 µg/mL) of BBR shows no apparent damage to the cell wall; red arrows point to the deposition of BBR crystals around the bacterial cell wall, with black crystalline material being BBR. (B) At high concentrations (512 µg/mL), there is significant damage to the cell wall structure and bacterial dissolution. Red arrows indicate the severe destruction and dissolution of the bacterial cell wall under high-concentration BBR treatment, along with extensive leakage of cellular contents, leading to bacterial lysis and death. (Microscope H-7650, acceleration voltage 80 kV)

Fig. 6

Network analysis of targets and signaling pathways of BBR in the treatment of MRSA. Note: (A) Number and characteristics of interactions between BBR and MRSA-related targets. (B) Interrelationships between BBR and essential biomolecules in MRSA through PPI network analysis. (C) Network visualization analysis of core genes, identifying critical genes related to MRSA survival and pathogenicity potentially affected by BBR. (D) KEGG enrichment analysis of the MRSA-related biological pathways influenced by BBR. (E) GO analysis of the biological processes, cellular components, and molecular functions impacted by BBR. Graphical abstract Illustration of the antimicrobial mechanism of BBR against MRSA