Menstrual toxic shock syndrome (mTSS) is a rare but severe disorder associated with the use of menstrual products such as high-absorbency tampons and is caused by strains that produce the toxic shock syndrome toxin-1 (TSST-1) superantigen. Herein, we screened a library of 3920 small bioactive molecules for the ability to inhibit transcription of the TSST-1 gene without inhibiting the growth of . The dominant positive regulator of TSST-1 is the SaeRS two-component system (TCS), and we identified phenazopyridine hydrochloride (PP-HCl) that repressed the production of TSST-1 by inhibiting the kinase function of SaeS. PP-HCl competed with ATP for binding of the kinase SaeS leading to decreased phosphorylation of SaeR and reduced expression of TSST-1 as well as several other secreted virulence factors known to be regulated by SaeRS. PP-HCl targets the virulence of , and it also decreases the impact of TSST-1 on human lymphocytes without affecting the healthy vaginal microbiota. Our findings demonstrate the promising potential of PP-HCl as a therapeutic strategy against mTSS.

中文翻译：

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发现一种针对金黄色葡萄球菌 SaeRS 双组分系统的抗毒化合物，可抑制中毒性休克综合征毒素 1 的产生


月经中毒性休克综合征 (mTSS) 是一种罕见但严重的疾病，与使用高吸收性卫生棉条等月经产品相关，由产生中毒性休克综合征毒素 1 (TSST-1) 超抗原的菌株引起。在此，我们筛选了 3920 个生物活性小分子的文库，以确定其抑制 TSST-1 基因转录而不抑制 生长的能力。 TSST-1 的显性正调节因子是 SaeRS 双组分系统 (TCS)，我们鉴定出盐酸非那吡啶 (PP-HCl) 通过抑制 SaeS 的激酶功能来抑制 TSST-1 的产生。 PP-HCl 与 ATP 竞争对激酶 SaeS 的结合，导致 SaeR 磷酸化减少，TSST-1 以及已知受 SaeRS 调节的其他几​​种分泌毒力因子的表达减少。 PP-HCl 针对 的毒力，并且还降低了 TSST-1 对人类淋巴细胞的影响，而不影响健康的阴道微生物群。我们的研究结果证明了 PP-HCl 作为 mTSS 治疗策略的巨大潜力。