TY - JOUR
T1 - Sorangicin A Is Active against Chlamydia in Cell Culture, Explanted Fallopian Tubes, and Topical In Vivo Treatment
AU - Graspeuntner, Simon
AU - Koethke, Katharina
AU - Scholz, Celeste
AU - Semmler, Lea
AU - Lupatsii, Mariia
AU - Kirchhoff, Laura
AU - Herrmann, Jennifer
AU - Rox, Katharina
AU - Wittstein, Kathrin
AU - Käding, Nadja
AU - Hanker, Lars C
AU - Stadler, Marc
AU - Brönstrup, Mark
AU - Müller, Rolf
AU - Shima, Kensuke
AU - Rupp, Jan
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/4/22
Y1 - 2023/4/22
N2 - Current treatment of Chlamydia trachomatis using doxycycline and azithromycin introduces detrimental side effects on the host's microbiota. As a potential alternative treatment, the myxobacterial natural product sorangicin A (SorA) blocks the bacterial RNA polymerase. In this study we analyzed the effectiveness of SorA against C. trachomatis in cell culture, and explanted fallopian tubes and systemic and local treatment in mice, providing also pharmacokinetic data on SorA. Potential side effects of SorA on the vaginal and gut microbiome were assessed in mice and against human-derived Lactobacillus species. SorA showed minimal inhibitory concentrations of 80 ng/mL (normoxia) to 120 ng/mL (hypoxia) against C. trachomatis in vitro and was eradicating C. trachomatis at a concentration of 1 µg/mL from fallopian tubes. In vivo, SorA reduced chlamydial shedding by more than 100-fold within the first days of infection by topical application corresponding with vaginal detection of SorA only upon topical treatment, but not after systemic application. SorA changed gut microbial composition during intraperitoneal application only and did neither alter the vaginal microbiota in mice nor affect growth of human-derived lactobacilli. Additional dose escalations and/or pharmaceutical modifications will be needed to optimize application of SorA and to reach sufficient anti-chlamydial activity in vivo.
AB - Current treatment of Chlamydia trachomatis using doxycycline and azithromycin introduces detrimental side effects on the host's microbiota. As a potential alternative treatment, the myxobacterial natural product sorangicin A (SorA) blocks the bacterial RNA polymerase. In this study we analyzed the effectiveness of SorA against C. trachomatis in cell culture, and explanted fallopian tubes and systemic and local treatment in mice, providing also pharmacokinetic data on SorA. Potential side effects of SorA on the vaginal and gut microbiome were assessed in mice and against human-derived Lactobacillus species. SorA showed minimal inhibitory concentrations of 80 ng/mL (normoxia) to 120 ng/mL (hypoxia) against C. trachomatis in vitro and was eradicating C. trachomatis at a concentration of 1 µg/mL from fallopian tubes. In vivo, SorA reduced chlamydial shedding by more than 100-fold within the first days of infection by topical application corresponding with vaginal detection of SorA only upon topical treatment, but not after systemic application. SorA changed gut microbial composition during intraperitoneal application only and did neither alter the vaginal microbiota in mice nor affect growth of human-derived lactobacilli. Additional dose escalations and/or pharmaceutical modifications will be needed to optimize application of SorA and to reach sufficient anti-chlamydial activity in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85160345807&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/6b3059a2-bffb-3e74-bb2c-b5f62ac4e9f3/
U2 - 10.3390/antibiotics12050795
DO - 10.3390/antibiotics12050795
M3 - Journal articles
C2 - 37237698
SN - 2079-6382
VL - 12
JO - Antibiotics (Basel, Switzerland)
JF - Antibiotics (Basel, Switzerland)
IS - 5
M1 - 795
ER -