Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630003, Tamil Nadu, India.
Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630003, Tamil Nadu, India; Department of Physiology and Biophysics, University of California, Irvine, CA 92697, United States.
Biomed Pharmacother. 2021 Sep;141:111933. doi: 10.1016/j.biopha.2021.111933. Epub 2021 Jul 26.
Staphylococcus aureus is a leading pathogen responsible for mild to severe invasive infections in humans. Especially, methicillin resistant Staphylococcus aureus (MRSA) is prevalent in hospital and community associated infections. Staphyloxanthin is a golden yellow color eponymous pigment produced by S. aureus and provides resistance to reactive oxygen species (ROS) and host neutrophil-based killing. In addition, this membrane pigment contributes to membrane rigidity and helps MRSA to survive under stress conditions. Targeting virulence of pathogen without exerting selection pressure is the recent approach to fight bacterial infections without developing drug resistance. The present study for the first time evaluated the staphyloxanthin inhibitory potential of thymol against MRSA. Qualitative and quantitative analyses demonstrated 90% of staphyloxanthin inhibition at 100 µg/mL concentration of thymol without alteration in growth. Molecular docking analysis and in vitro measurement of metabolic intermediates of staphyloxanthin revealed that thymol could possibly interact with CrtM to inhibit staphyloxanthin. Absorbance and infra red spectra further validated the inhibition of staphyloxanthin by thymol. In addition, thymol treatment significantly reduced the resistance of MRSA to ROS and neutrophil-based killing as exhibited by oxidant susceptibility assays and ex vivo innate immune clearance assay using human whole blood and neutrophils. Further, reduction in staphyloxanthin by thymol treatment increased the membrane fluidity and made MRSA cells more susceptible to membrane targeting antibiotic polymyxin B. Especially, thymol was found to be non-cytotoxic to human peripheral blood mononuclear cells. Our study validated the antivirulence potential of thymol against MRSA by inhibiting staphyloxanthin and suggests the prospective therapeutic role of thymol to combat MRSA infections.
金黄色葡萄球菌是一种主要的病原体，可导致人类轻度至重度侵袭性感染。特别是耐甲氧西林金黄色葡萄球菌（MRSA）在医院和社区相关感染中普遍存在。金黄色素是金黄色葡萄球菌产生的一种金黄色标志性色素，可抵抗活性氧（ROS）和宿主中性粒细胞介导的杀伤。此外，这种膜色素有助于膜刚性，并帮助 MRSA 在应激条件下存活。在不产生选择压力的情况下靶向病原体的毒力是目前对抗细菌感染而不产生耐药性的方法。本研究首次评估了百里香酚对 MRSA 金黄色素的抑制潜力。定性和定量分析表明，在 100μg/ml 浓度的百里香酚作用下，金黄色素抑制率达到 90%，而生长无变化。分子对接分析和金黄色素代谢中间产物的体外测量表明，百里香酚可能与 CrtM 相互作用以抑制金黄色素。吸光度和红外光谱进一步验证了百里香酚对金黄色素的抑制作用。此外，百里香酚处理显著降低了 MRSA 对 ROS 和中性粒细胞介导的杀伤的耐药性，如氧化剂敏感性测定和使用人全血和中性粒细胞的体外固有免疫清除测定所显示的。此外，百里香酚处理减少金黄色素使 MRSA 细胞对膜靶向抗生素多粘菌素 B 更敏感。特别是，百里香酚对人外周血单核细胞没有细胞毒性。我们的研究通过抑制金黄色素验证了百里香酚对 MRSA 的抗病毒潜力，并表明百里香酚在对抗 MRSA 感染方面具有潜在的治疗作用。
