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

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 bacte...

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Published in:	mBio Vol. 6; no. 1; pp. e02304 - e02314
Main Authors:	Engström, Patrik, Krishnan, K Syam, Ngyuen, Bidong D, Chorell, Erik, Normark, Johan, Silver, Jim, Bastidas, Robert J, Welch, Matthew D, Hultgren, Scott J, Wolf-Watz, Hans, Valdivia, Raphael H, Almqvist, Fredrik, Bergström, Sven
Format:	Journal Article
Language:	English
Published:	United States American Society of Microbiology 30-12-2014 American Society for Microbiology
Subjects:	Carbohydrate Metabolism - drug effects Chlamydia trachomatis - drug effects Chlamydia trachomatis - metabolism DNA Mutational Analysis Drug Resistance, Bacterial Enzyme Inhibitors - metabolism Escherichia coli - drug effects Glucose-6-Phosphate - metabolism HeLa Cells - drug effects Humans Mutation Pyridones - metabolism
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Summary:	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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 K.S.K. and B.D.N. contributed equally to this work.
ISSN:	2161-2129 2150-7511 2150-7511
DOI:	10.1128/mBio.02304-14