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Published on: September 8, 2021
Effect of Three Different Amino Acids Plus Gentamicin Against Methicillin-Resistant Staphylococcus aureus
Juan Guo1, Zhiyu Pan1, Lvyuan Fan1
1Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, People's Republic of China.
Background:
The issue of methicillin-resistant Staphylococcus aureus (MRSA) resistant to many antibiotics and causing serious infectious diseases is a growing healthcare concern.
Purpose:
In recent years, exogenous administration of metabolites in combination with antibiotics can re-sensitize resistant bacteria to antibiotics; however, their effects vary, and their underlying mechanism of action remains elusive.
Methods:
We assessed the bactericidal effects of the three amino acids in combination with gentamicin in vitro and in vivo. Subsequently, we explored the role of these amino acids on the metabolomics of MRSA using Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we performed the downstream analyses using MetaboAnalyst and Interactive Pathways Explorer.
Results:
Exogenous threonine showed the best bactericidal efficacy with gentamicin, followed by glycine, wherein serine had no effect. Amino acid treatments mainly up-regulated the metabolites, increased the amino acid abundance, and significantly activated metabolisms; these effects were consistent with the bactericidal efficacy of the three amino acids. Most amino acids participated in the tricarboxylic acid cycle, and threonine supplementation increased the activities of citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, whereas glycine increased activities of citrate synthase and α-ketoglutarate dehydrogenase, and serine did not affect the activities of any of the three key enzymes. We identified 24 biomarkers in the three groups, among which glutamic acid and cysteine showed a gradient decrease and increase, respectively. Subsequent analyses revealed that glutamic acid but not cysteine promoted the bactericidal effect of gentamicin synergistically.
Conclusion:
Threonine has the best synergistic effect in reversing bacterial resistance compared to glycine and serine. We show that different amino acids combined with an antibiotic mainly affect amino acid metabolism and act via different metabolic regulatory mechanisms, which could help develop effective strategies for tackling MRSA infections.
Insights
Threonine and glycine, but not serine, enhance gentamicin's effectiveness against methicillin-resistant Staphylococcus aureus (MRSA). These amino acids alter MRSA metabolism, with threonine showing the strongest synergistic effect in combating antibiotic resistance.
Area of Science:
- Microbiology
- Metabolomics
- Drug Discovery
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant healthcare challenge due to its resistance to multiple antibiotics.
- Developing novel strategies to combat MRSA infections is crucial.
Purpose of the Study:
- To investigate the potential of exogenous amino acids to re-sensitize MRSA to antibiotics.
- To elucidate the metabolic mechanisms underlying the synergistic effects of amino acids and antibiotics.
Main Methods:
- Assessed the bactericidal effects of threonine, glycine, and serine in combination with gentamicin against MRSA in vitro and in vivo.
- Utilized Liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze MRSA metabolomics.
- Performed downstream analyses using MetaboAnalyst and Interactive Pathways Explorer.
Main Results:
- Threonine demonstrated the most potent bactericidal effect when combined with gentamicin, followed by glycine; serine showed no significant effect.
- Amino acid treatments generally upregulated metabolites and activated metabolic pathways, correlating with their observed bactericidal efficacy.
- Threonine and glycine supplementation modulated key enzymes in the tricarboxylic acid cycle, while glutamic acid was identified as a synergistic biomarker.
Conclusions:
- Threonine exhibits the strongest synergistic effect in overcoming MRSA antibiotic resistance compared to glycine and serine.
- The combination of specific amino acids with antibiotics impacts amino acid metabolism through distinct regulatory mechanisms.
- These findings offer potential avenues for developing novel therapeutic strategies against MRSA infections.
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