A 2-pyridone-amide inhibitor targets the glucose metabolism pathway of Chlamydia trachomatis

Patrik Engström, K. Syam Krishnan, Bidong D. Ngyuen, Erik Chorell, Johan Normark, Jim Silver, Robert J. Bastidas, Matthew D. Welch, Scott J. Hultgren, Hans Wolf-Watz, Raphael H. Valdivia, Fredrik Almqvist, Sven Bergström

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Abstract

In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). 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. IMPORTANCE 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. Here, by using a visual screen for compounds that affect 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 suggest 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.

Original languageEnglish
Article numbere02304
JournalmBio
Volume6
Issue number1
DOIs
StatePublished - Dec 30 2014

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    Engström, P., Syam Krishnan, K., Ngyuen, B. D., Chorell, E., Normark, J., Silver, J., Bastidas, R. J., Welch, M. D., Hultgren, S. J., Wolf-Watz, H., Valdivia, R. H., Almqvist, F., & Bergström, S. (2014). A 2-pyridone-amide inhibitor targets the glucose metabolism pathway of Chlamydia trachomatis. mBio, 6(1), [e02304]. https://doi.org/10.1128/mBio.02304-14