Impact of metabolic changes triggered by microenvironmental factors on the efficacy of antimicrobials against Chlamydia trachomatis

• Applicant: Dr. Inga Kaufhold
• Subject Area: Reproductive Medicine, Urology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 299233299

Urogenital tract infections with Chlamydia trachomatis are the most prevalent bacterial sexually transmitted diseases worldwide. C. trachomatis recurrent or persistent infections can lead to serious sequelae such as pelvic inflammatory disease (PID), ectopic pregnancy and infertility. Doxycycline and azithromycin are first-line drugs in treating C. trachomatis infection. However, treatment failures occur in around 8% of the patients. The reason is not yet completely understood and we wonder what kind of bacterial and host factors associate with treatment failures. A transient form of decreased susceptibility of antibiotics in the absence of a genetic change has been described for extracellular bacteria. In this form of phenotypic resistance changes in the bacterial metabolism seem to influence the antimicrobial efficacy. Phenotypic resistance in chlamydial infection was reported in vitro in the chlamydial persistent state or under low oxygen conditions (2% O2). It was shown that C. trachomatis in these growth states is less susceptible to antibiotics. However, the mechanism of this are still poorly investigated. As an obligate-intracellular bacteria C. trachomatis have a reduced genome size harboring incomplete metabolic pathways. Therefore C. trachomatis depend on host metabolites. Certain stimuli inducing chlamydial persistence such as Interferon-gamma are associated with changes in the energy metabolism of the host cell. In addition, low oxygen conditions (hypoxia, 2% O2) influence the host cell metabolism in which they stimulated the glycolysis and production of lactate. Moreover, an increased proton production accounts for a drop in the pH value. While it has been reported that an altered pH directly affected the antibiotic efficacy against extracellular bacterial uropathogens, it is so far not known how the metabolic activity or an alteration in the pH impacts the antibiotic efficacy against intracellular C. trachomatis. Therefore, we will define host metabolic regulation mechanisms upon mircoenvironmental factors that influence the antibiotic efficacy against C. trachomatis. On this basis new antibiotic treatment strategies to increase the effectiveness of antibiotics can be obtained to counteract possible treatment failures of C. trachomatis infections.

• DFG Programme: Research Grants