MoLife Research Seminar by:
Prof. Dr. Sven Bergström, Umeå University, Department of Molecular Biology, Schweden
Title of the talk:
Chemical genetics to investigate Chlamydia trachomatis biology and pathogenesis
Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Using a visual screen for compounds that affects bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggests that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections. Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. Bacterial replication and the generation of infectious progeny are the hallmarks of efficient pathogenesis for Chlamydia. In a recent study we describe a novel mechanism for Chlamydial attenuation, through the inhibition of a host cell signalling pathway. We show that inhibition of ERK signalling by small molecule inhibitors result in production of non-infectious Chlamydia progeny. Thus, the 2-pyridone amide compounds were shown to inhibit ERK signalling and were an effective treatment of vaginal chlamydia infections in a murine model. The 2-pyridone amide ERK-inhibitors were non-toxic to host cells and present a novel treatment approach for intracellular infections.
Engström et al mBio 2014 Dec 30;6(1):e02304-14. doi: 10.1128/mBio.02304-14.A 2-pyridone-amide inhibitor targets the glucose metabolism pathway of Chlamydia trachomatis.
Engström et al Int J Med Microbiol. 2015 May;305(3):378-82.
doi: 10.1016/j.ijmm.2015.02.007. Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication
Good JA et al 2016, J Med Chem. 2016 Mar 10;59(5):2094-108. doi:10.1021/acs.jmedchem.5b01759. Thiazolino 2-pyridone amide inhibitors of Chlamydia trachomatis infectivity