Antimicrobial resistance is the greatest threat to the treatment of bacterial infectious diseases. The development of resistance-modifying agents (RMAs) represents a promising strategy to mitigate the spread of bacterial antimicrobial resistance. In this study, a natural product, isovalerylshikonin (IVS), was isolated from Arnebia euchroma, a traditional Chinese medicine herb, that exhibited marginal antibacterial activity against drug-resistant Staphylococcus aureus RN4220, with a minimum inhibitory concentration (MIC) of 16 mg/L. In addition, a synergistic effect between IVS and streptomycin (STM) was detected by the microdilution antimicrobial chequerboard assay, with a reduction in the MIC of STM by up to 16-fold against strain RN4220. A bacterial ethidium bromide efflux assay and reverse transcription PCR were performed to investigate the synergistic mechanism. IVS significantly inhibited bacterial efflux and expression of msrA mRNA in vitro. A murine peritonitis/sepsis model was employed to test the in vivo synergistic activity of IVS and STM. IVS synergistically decreased bacterial counts with STM in peritoneal, spleen and liver tissue and increased mouse survival with STM in 7 days. The acute toxicity of IVS was tested and the 50% lethal dose (LD50) of IVS with a single exposure was 2.584 g/kg in mice. Overall, IVS, a low-toxicity RMA, exhibited synergistic antibacterial activities in vitro and in vivo against drug-resistant S. aureus. The effects were mediated by suppression of msrA mRNA expression and reduced bacterial efflux. In addition, these data support that IVS is a potential RMA against microbial resistance caused by the MsrA efflux pump.

中文翻译：

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紫草中的一种新的抗药性改良剂异戊酸紫草苷可抑制耐药性金黄色葡萄球菌的抗生素耐药性

抗菌素耐药性是细菌感染性疾病治疗的最大威胁。耐药修饰剂（RMA）的开发代表了缓解细菌耐药性传播的一种有前途的策略。在这项研究中，从中草药紫草中分离出一种天然产物异戊基紫草素（IVS），其对耐药性金黄色葡萄球菌RN4220表现出有限的抗菌活性，最低抑菌浓度（MIC）为16 mg / L. 此外，通过微稀释抗微生物棋盘试验检测到IVS和链霉素（STM）之间的协同作用，相对于RN4220菌株，STM的MIC降低了16倍。进行了细菌溴化乙锭外排试验和逆转录PCR研究了这种协同机制。IVS在体外显着抑制细菌外排和msrA mRNA的表达。使用鼠腹膜炎/败血症模型来测试IVS和STM的体内协同活性。IVS与腹膜，脾脏和肝脏组织中的STM协同减少细菌计数，并在7天内通过STM协同增加小鼠存活率。测试了IVS的急性毒性，单次暴露的IVS的50％致死剂量（LD50）在小鼠中为2.584 g / kg。总体而言，IVS是一种低毒的RMA，在体外和体内对耐药性金黄色葡萄球菌均表现出协同抗菌活性。这些作用是通过抑制msrA mRNA表达和减少细菌外排介导的。此外，