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

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.