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Abstract：
Staphylococcus aureus is a highly prevalent and aggressive human pathogen causing a wide range of infections. This study aimed to explore the potential of Patuletin, a rare natural flavone, as an anti-virulence agent against S. aureus. At a sub-inhibitory concentration (1/4 MIC), Patuletin notably reduced biofilm formation by 27 % and 23 %, and decreased staphyloxanthin production by 53 % and 46 % in Staphylococcus aureus isolate SA25923 and clinical isolate SA1, respectively. In order to gain a more comprehensive understanding of the in vitro findings, several in silico analyses were conducted. Initially, a 3D-flexible alignment study demonstrated a favorable structural similarity between Patuletin and B70, the co-crystallized ligand of CrtM, an enzyme that plays a pivotal role in the biosynthesis of staphyloxanthin. Molecular docking highlighted the strong binding of Patuletin to the active site of CrtM, with a high affinity of -20.95 kcal/mol. Subsequent 200 ns molecular dynamics simulations, along with MM-GBSA, ProLIF, PLIP, and PCAT analyses, affirmed the stability of the Patuletin-CrtM complex, revealing no significant changes in CrtM\'s structure upon binding. Key amino acids crucial for binding were also identified. Collectively, this study showcased the effective inhibition of CrtM activity by Patuletin in silico and its attenuation of key virulence factors in vitro, including biofilm formation and staphyloxanthin production. These findings hint at Patuletin\'s potential as a valuable therapeutic agent, especially in combination with antibiotics, to counter antibiotic-resistant Staphylococcus aureus infections.
摘要：
金黄色葡萄球菌是引起广泛感染的高度流行和侵袭性人类病原体。本研究旨在探索Patustin的潜力，一种稀有的天然黄酮，作为抗金黄色葡萄球菌的抗毒剂。在亚抑制浓度（1/4MIC），Patudetin显着减少了27％和23％的生物膜形成，在金黄色葡萄球菌分离株SA25923和临床分离株SA1中，分别减少了53％和46％。为了更全面地了解体外研究结果，进行了几次计算机模拟分析。最初，3D灵活的比对研究表明，Patudetin和B70之间具有良好的结构相似性，B70是CrtM的共结晶配体，一种在葡萄黄质生物合成中起关键作用的酶。分子对接强调了Patudetin与CrtM活性位点的强结合，具有-20.95kcal/mol的高亲和力。随后的200ns分子动力学模拟，随着MM-GBSA，ProLIF,PLIP,和PCAT分析，肯定了Patutin-CrtM复合物的稳定性，结合后CrtM的结构没有明显变化。还鉴定了对于结合至关重要的关键氨基酸。总的来说，本研究展示了Patuletin对CrtM活性的有效抑制及其对关键毒力因子的体外减毒作用，包括生物膜的形成和葡萄黄质的生产。这些发现暗示了Patutynetin作为一种有价值的治疗剂的潜力，尤其是与抗生素联合使用，对抗耐抗生素金黄色葡萄球菌感染。
