Sorangicin A as a Topic Antibiotic Treatment Option Against Vaginal C. trachomatis Infection. undefined

Genital tract infections with Chlamydia trachomatis are the most frequent bacterial sexually transmitted disease (STD) worldwide. Current treatment regimens include doxycycline and azithromycin, which are both orally applied in infected patients. So far, no topical therapies, are available. The myxobacterial natural product sorangicin A (SorA) blocks the bacterial RNA polymerase (RNAP) and is proven to be active against other intracellular bacteria such as Mycobacterium tuberculosis. In this study we analyzed the effectiveness of SorA against C. trachomatis in various infection models. We tested SorA efficacy under conventional normoxic conditions but also under physiological relevant oxygen concentration (hypoxia, 2 % O2) that is found in the urogenital tract of females. Besides testing SorA in cell culture, an ex vivo human fallopian tube tissue model and in vivo infection experiments in mice were conducted. In the latter experiments, pharmacokinetic characteristics of SorA in the murine vagina as well as SorA-mediated side effects on the intestinal microbiota were analyzed. SorA showed minimal inhibitory concentrations of 80 ng/ml (normoxia) to 120 ng/ml (hypoxia) against C. trachomatis in vitro. Tissue culture experiments displayed significant eradication of C. trachomatis at 1 µg/ml SorA. Our in vivo mouse model revealed that SorA significantly reduced chlamydial shedding, more efficiently by topic than by systemic application. SorA reached concentrations of 84.9 - 230.1 µg/g in vaginal tissue and accumulates during topical treatment over time, but not after systemic application. Microbiota analysis showed effects on gut microbial composition only during intraperitoneal SorA treatment. In summary, without additional dose escalations and/or pharmaceutical modifications, systemic application of SorA does not reach sufficient anti-chlamydial activity. Whereas topical application in the vagina, however, effectively reduced chlamydial shedding without having profound side-effects on the gut microbiome.

沙眼衣原体（Chlamydia trachomatis）引发的生殖道感染是全球范围内最常见的细菌性性传播疾病（STD）。当前临床治疗方案包括多西环素与阿奇霉素，二者均通过口服途径给药用于感染患者。截至目前，暂无可用的局部治疗手段。黏杆菌来源天然产物索朗吉星A（Sorangicin A，SorA）可阻断细菌RNA聚合酶（RNAP），且已被证实对结核分枝杆菌（Mycobacterium tuberculosis）等其他胞内致病菌具有抗菌活性。本研究旨在评估SorA对沙眼衣原体在多种感染模型中的抗菌效果。我们分别在常规常氧条件，以及女性泌尿生殖道内存在的生理相关氧浓度环境（缺氧条件，2% O₂）下测试了SorA的抗菌活性。除细胞培养实验外，本研究还构建了人输卵管组织离体模型，并开展了小鼠体内感染实验。在上述体内实验中，我们分析了SorA在小鼠阴道内的药代动力学特征，以及SorA对肠道菌群的介导性副作用。体外实验结果显示，SorA对沙眼衣原体的最低抑菌浓度为80 ng/ml（常氧条件）至120 ng/ml（缺氧条件）。细胞培养实验证实，1 µg/ml的SorA即可显著清除沙眼衣原体。小鼠体内感染模型实验结果显示，SorA可显著降低衣原体排菌量，且局部给药的效果优于全身给药。SorA在阴道组织中的浓度可达84.9–230.1 µg/g，且在局部给药过程中随时间推移出现蓄积，但全身给药时未观察到此现象。肠道菌群分析结果显示，仅在腹腔内给予SorA时，才会对肠道微生物组成产生影响。综上，在不额外增加给药剂量或进行药物修饰的前提下，全身给药无法达到足够的抗沙眼衣原体活性。而阴道局部给药则可有效降低衣原体排菌量，且不会对肠道微生物组产生显著副作用。