Abstract
The treatment of Staphylococcus aureus (S. aureus) infections has become more difficult due to the emergence of multidrug resistance in the bacteria. Here, we report the synthesis of a lawsone (2-hydroxy-1,4-naphthoquinone)-based compound as an antimicrobial agent against methicillin-resistant S. aureus (MRSA). A series of lawsone-derivative compounds were synthesized by means of tuning the lipophilicity of lawsone and screened for minimum inhibitory concentrations against MRSA to identify a candidate compound that possesses a potent antibacterial activity. The identified lawsone-derivative compound exhibited significantly improved drug resistance profiles against MRSA compared to conventional antibiotics. The therapeutic efficacy of the compound was validated using murine models of wound infection as well as non-lethal systemic infection induced by MRSA. Our study further revealed the multifaceted modes of action of the compound, mediated by three distinctive mechanisms: (1) cell membrane damage, (2) chelation of intracellular iron ions, and (3) generation of intracellular reactive oxygen species.
Highlights
The treatment of Staphylococcus aureus (S. aureus) infections has become more difficult due to the emergence of multidrug resistance in the bacteria
The 6c was effective against vancomycin-intermediate S. aureus (VISA) (ATCC 700699) that is non-susceptible to daptomycin (MIC = 4 μg/mL), with the same minimum inhibitory concentrations (MICs) value against methicillin-resistant S. aureus (MRSA)
In this study, we report the synthesis of a lawsone-based synthetic antimicrobial compound (6c) that exhibits a potent antimicrobial activity as well as improved drug resistance profile against MRSA
Summary
The treatment of Staphylococcus aureus (S. aureus) infections has become more difficult due to the emergence of multidrug resistance in the bacteria. Staphylococcus aureus (S. aureus) is a Gram-positive human pathogen causing a variety of diseases ranging from softtissue infections to life-threatening diseases such as endocarditis, toxic shock syndrome, and necrotizing pneumonia[1] The treatment of these infections has become more difficult due to the emergence of multidrug resistant strains, along with their ability to evade attack by the host innate immune system, which renders the treatment of methicillin-resistant S. aureus (MRSA) critical challenges[2,3]. Since iron homeostasis is critical for the survival of bacterial cells, interception of intracellular transitory iron or demetallation of iron-containing proteins and enzymes by such chelating ligand can be detrimental for bacterial cells[16,17] These unique characteristics of lawsone have not been explored for developing new antimicrobial compounds to the best of our knowledge. Our findings present an opportunity to utilize the unique mode of action of lawsone derivative in the development of synthetic compounds as an antibacterial strategy that can decrease the likelihood of bacterial resistance
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