Drug Information

Drug (ID: DG02166) and It's Reported Resistant Information

• Name: Alpha-Mangostin-4
• Synonyms: alpha-Mangostin-4
• Indication:
  In total 1 Indication(s)
  . .; .; [1]

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Staphylococcus meningitis [ICD-11: 1B54]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multiple efflux pumps MepA and NorA [1]

• Sensitive Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Efflux pumps of MRSA2 signaling pathway; Regulation; N.A.
• In Vitro Model: Male SPF-grade ICR mice; 5833
• In Vitro Model: Methicillin-resistant Staphylococcus aureus; 5833
• Experiment for Molecule Alteration: SEM assay; TEM assay; EtBr accumulation assay; qRT-PCR; Western blot assay; Bocillin FL PBP binding assay; beta-Lactamase activity assay
• Experiment for Drug Resistance: MIC assay; Time-Kill assay; Hemolytic activity assay; Cytotoxicity assay
• Mechanism Description: In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized alpha-mangostin (alpha-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. alpha-MG-4, featuring an allyl group at C3 of the lead compound alpha-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although alpha-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that alpha-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. alpha-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA)'s resistance to multiple antibiotics poses significant health and safety concerns. A novel alpha-mangostin (alpha-MG) derivative, alpha-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of alpha-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.

References

• Ref 1: A novel alpha-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms. Microbiol Spectr. 2024 Nov 7;12(12):e0163124.