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Abstract：
Sortase A (SrtA) is a cysteine transpeptidase that binds to the periplasmic membrane and plays a crucial role in attaching surface proteins, including staphylococcal protein A (SpA), to the peptidoglycan cell wall. Six pentacyclic polyketides (1-6) were isolated from the marine sponge Xestospongia sp., and their structures were elucidated using spectroscopic techniques and by comparing them to previously reported data. Among them, halenaquinol (2) was found to be the most potent SrtA inhibitor, with an IC50 of 13.94 μM (4.66 μg/mL). Semi-quantitative reverse transcription PCR data suggest that halenaquinol does not inhibit the transcription of srtA and spA, while Western blot analysis and immunofluorescence microscopy images suggest that it blocks the cell wall surface anchoring of SpA by inhibiting the activity of SrtA. The onset and magnitude of the inhibition of SpA anchoring on the cell wall surface in S. aureus that has been treated with halenaquinol at a value 8× that of the IC50 of SrtA are comparable to those for an srtA-deletion mutant. These findings contribute to the understanding of the mechanism by which marine-derived pentacyclic polyketides inhibit SrtA, highlighting their potential as anti-infective agents targeting S. aureus virulence.
摘要：
分选酶A（SrtA）是一种半胱氨酸转肽酶，与周质膜结合，在附着表面蛋白中起着至关重要的作用，包括葡萄球菌蛋白A（SpA），肽聚糖细胞壁。从海洋海绵Xestospongiasp.中分离出六个五环聚酮化合物（1-6）。,并使用光谱技术并将其与先前报道的数据进行比较来阐明它们的结构。其中,发现卤喹醇（2）是最有效的SrtA抑制剂，IC50为13.94μM(4.66μg/mL)。半定量逆转录PCR数据表明，卤代喹醇不抑制srtA和spA的转录，而Western印迹分析和免疫荧光显微镜图像表明，它通过抑制SrtA的活性来阻断SpA的细胞壁表面锚定。在用卤代喹醇处理的金黄色葡萄球菌中，SpA锚定在细胞壁表面上的抑制作用的开始和幅度与srtA缺失突变体的IC50的8倍相当。这些发现有助于理解海洋衍生的五环聚酮化合物抑制SrtA的机制，突出了它们作为针对金黄色葡萄球菌毒力的抗感染药的潜力。
