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Effective Membrane Permeabilization of Methicillin-Resistant Staphylococcus aureus by Prenylated Phenolics
Janniek H Ritsema1,2, Nynke I Kramer2, Wouter J C de Bruijn1
1Laboratory of Food Chemistry, Wageningen University, Bornse Weilanden 9, 6708 WG Wageningen, Netherlands.
Abstract:
Prenylated phenolics are plant-derived compounds with antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), acting by targeting membranes resulting in fast permeabilization. Studies quantifying their membrane permeabilization capacity are lacking, limiting our understanding of the structural properties driving this effect. This study evaluated antimicrobial activity and permeabilization efficacy of 36 C- and O-prenylated phenolics, including 11 C- and O-prenylated phenolics chemically synthesized for this study. Minimum inhibitory concentrations (MICs) were obtained using the broth microdilution assay. Membrane permeabilization was measured by propidium iodide uptake using fluorescence spectrometry and microscopy. The most potent MRSA permeabilizers were luteone (29) and neobavaisoflavone (22), with EC10 of 27 ± 7 and 28 ± 8 μg mL-1, respectively. Diprenylated phenolics showed a strong negative correlation between permeabilization and their hydrophobic-to-polar surface area ratio (rpearson = 0.88). For monoprenylated phenolics, prenyl configuration (chain) and molecular shape (globular) were important for effective permeabilization. Interestingly, potency of antimicrobial prenylated phenolics (MIC ≤ 50 μg mL-1) was not correlated to permeabilization potency, suggesting other mechanisms of action in addition to membrane permeabilization. These quantitative findings on membrane permeabilization by prenylated phenolics contribute to our mechanistic understanding of how these compounds can inhibit microbial growth.
Insights
Prenylated phenolics disrupt bacterial membranes, with luteone and neobavaisoflavone being potent agents against methicillin-resistant Staphylococcus aureus (MRSA). Structure influences permeabilization, but antimicrobial potency doesn't always correlate with this effect.
Area of Science:
- Natural Product Chemistry
- Microbiology
- Pharmacology
Background:
- Prenylated phenolics possess antimicrobial properties against methicillin-resistant Staphylococcus aureus (MRSA).
- Their mechanism involves targeting bacterial membranes, leading to rapid permeabilization.
- Quantitative data on the membrane permeabilization capacity of these compounds are limited.
Purpose of the Study:
- To evaluate the antimicrobial activity and membrane permeabilization efficacy of various prenylated phenolics against MRSA.
- To identify structural features that enhance membrane permeabilization.
- To investigate the relationship between antimicrobial potency and membrane permeabilization capacity.
Main Methods:
- Synthesized 11 novel C- and O-prenylated phenolics.
- Assessed antimicrobial activity using broth microdilution to determine Minimum Inhibitory Concentrations (MICs).
- Measured membrane permeabilization via propidium iodide uptake using fluorescence spectrometry and microscopy.
Main Results:
- Luteone and neobavaisoflavone were the most effective MRSA membrane permeabilizers (EC10 of 27 ± 7 and 28 ± 8 μg mL⁻¹, respectively).
- Diprenylated phenolics showed a strong negative correlation between permeabilization and hydrophobicity (r = 0.88).
- Monoprenylated phenolics' permeabilization depended on prenyl chain configuration and molecular shape.
- Antimicrobial potency (MIC ≤ 50 μg mL⁻¹) did not correlate with membrane permeabilization potency, suggesting additional mechanisms of action.
Conclusions:
- This study quantifies the membrane permeabilization capacity of prenylated phenolics.
- Structural characteristics significantly influence the ability of these compounds to permeabilize bacterial membranes.
- The lack of correlation between antimicrobial potency and permeabilization suggests multifaceted mechanisms of action for prenylated phenolics against MRSA.
