Antibacterial Effects of Glycyrrhetinic Acid and Its Derivatives on <i>Staphylococcus aureus</i>

Staphylococcus aureus is a major pathogen in humans and causes serious problems due to antibiotic resistance. We investigated the antimicrobial effect of glycyrrhetinic acid (GRA) and its derivatives against 50 clinical S. aureus strains, including 18 methicillin-resistant strains. The minimum inhibitory concentrations (MICs) of GRA, dipotassium glycyrrhizate, disodium succinoyl glycyrrhetinate (GR-SU), stearyl glycyrrhetinate and glycyrrhetinyl stearate were evaluated against various S. aureus strains. Additionally, we investigated the bactericidal effects of GRA and GR-SU against two specific S. aureus strains. DNA microarray analysis was also performed to clarify the mechanism underlying the antibacterial activity of GR-SU. We detected the antimicrobial activities of five agents against S. aureus strains. GRA and GR-SU showed strong antibacterial activities compared to the other three agents tested. At a higher concentration (above 2x MIC), GRA and GR-SU showed bactericidal activity, whereas at a concentration of 1x MIC, they showed a bacteriostatic effect. Additionally, GRA and GR-SU exhibited a synergistic effect with gentamicin. The expression of a large number of genes (including transporters) and metabolic factors (carbohydrates and amino acids) was altered by the addition of GR-SU, suggesting that the inhibition of these metabolic processes may influence the degree of the requirement for carbohydrates or amino acids. In fact, the requirement for carbohydrates or amino acids was increased in the presence of either GRA or GR-SU. GRA and GR-SU exhibited strong antibacterial activity against several S. aureus strains, including MRSA. This activity may be partly due to the inhibition of several pathways involved in carbohydrate and amino acid metabolism.金黄色葡萄球菌（Staphylococcus aureus）是人类主要致病菌之一，其抗生素耐药性问题已引发严重公共健康隐患。本研究针对50株临床分离的金黄色葡萄球菌（含18株耐甲氧西林菌株），考察了甘草次酸（glycyrrhetinic acid, GRA）及其衍生物的抗菌活性。我们对五种受试物质——甘草次酸、甘草酸二钾、琥珀酰甘草次酸二钠（GR-SU）、硬脂酰甘草次酸酯以及甘草次酸硬脂酸酯——针对不同金黄色葡萄球菌菌株的最低抑菌浓度（minimum inhibitory concentrations, MICs）进行了评估。此外，本研究还针对两株特定的金黄色葡萄球菌菌株，考察了甘草次酸与GR-SU的杀菌活性。为阐明GR-SU发挥抗菌活性的分子机制，本研究同时开展了DNA微阵列分析。本研究检测了五种受试药剂对金黄色葡萄球菌菌株的抗菌活性：相较于其余三种受试药剂，甘草次酸与GR-SU展现出更优异的抗菌活性。当受试浓度高于2倍最低抑菌浓度（2×MIC）时，甘草次酸与GR-SU可表现出杀菌活性；而当浓度为1倍最低抑菌浓度（1×MIC）时，二者仅呈现抑菌效果。此外，甘草次酸与GR-SU与庆大霉素联用可产生协同抗菌作用。GR-SU处理可改变大量基因（包括转运蛋白编码基因）及代谢相关因子（碳水化合物与氨基酸代谢相关因子）的表达水平，提示抑制上述代谢过程可能会影响菌体对碳水化合物或氨基酸的需求程度。实际检测结果显示，当培养基中添加甘草次酸或GR-SU时，金黄色葡萄球菌对碳水化合物或氨基酸的需求均有所提升。甘草次酸与GR-SU对包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的多株金黄色葡萄球菌均展现出较强的抗菌活性，该活性部分可能源于其对碳水化合物与氨基酸代谢相关通路的抑制作用。