A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms

Autor: Rile Ge, Haiyan Zhao, Qun Tang, Kasemsiri Chandarajoti, Han Bai, Xiaoyang Wang, Keyu Zhang, Wenchong Ye, Xiangan Han, Chunmei Wang, Wen Zhou
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Microbiology Spectrum, Vol 12, Iss 12 (2024)
Druh dokumentu: article
ISSN: 2165-0497
39102939
DOI: 10.1128/spectrum.01631-24
Popis: ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. α-MG-4, featuring an allyl group at C3 of the lead compound α-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although α-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 α-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. α-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 α-mangostin (α-MG) derivative, α-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of α-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.
Databáze: Directory of Open Access Journals
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