Elaborations on Corallopyronin A as a Novel Treatment Strategy Against Genital Chlamydial Infections

Abstract

Ascending <i>Chlamydia trachomatis</i> infection causes functional damage to the fallopian tubes, which may lead to ectopic pregnancy and infertility in women. Treatment failures using the standard regimens of doxycycline and azithromycin have been observed. We tested the polyketide-derived α-pyrone antibiotic Corallopyronin A (CorA) that inhibits the bacterial DNA dependent RNA polymerase and has strong activity against various extracellular and some intracellular bacteria. Extensive testing in cell culture infection models and in an <i>ex vivo</i> human fallopian tube model under different oxygen concentrations was performed to assess the anti-chlamydial efficacy of CorA at physiological conditions. CorA showed high efficacy against <i>C. trachomatis</i> (MIC_N/H: 0.5 μg/mL for serovar D and L2), <i>C. muridarum</i> (MIC_N/H: 0.5 μg/mL), and <i>C. pneumoniae</i> (MIC_N/H: 1 μg/mL) under normoxic (N) and hypoxic (H) conditions. Recoverable inclusion forming units were significantly lower already at 0.25 μg/mL for all tested chlamydiae. CorA at a concentration of 1 μg/mL was also effective against already established <i>C. trachomatis</i> and <i>C. pneumoniae</i> infections (up to 24 h.p.i.) in epithelial cells, while efficacy against <i>C. muridarum</i> was limited to earlier time points. A preliminary study using a <i>C. muridarum</i> genital infection model revealed corresponding limitations in the efficacy. Importantly, in an <i>ex vivo</i> human fallopian tube model, the growth of <i>C. trachomatis</i> was significantly inhibited by CorA at concentrations of 1-2 μg/mL under normoxic and hypoxic conditions. The overall high efficacies of CorA against <i>C. trachomatis</i> in cell culture and an <i>ex vivo</i> human fallopian tube model under physiological oxygen concentrations qualifies this drug as a candidate that should be further investigated.