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

Abstract

UNLABELLED:

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.

• Authors: 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
• Journal: mBio (mBio) Vol. 6 Issue 1 Pg. e02304-14 (Dec 30 2014) ISSN: 2150-7511 [Electronic] United States
• PMID: 25550323 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Engström et al.

Chemical References

• Enzyme Inhibitors
• Pyridones
• Glucose-6-Phosphate
• 2-hydroxypyridine

Topics

• Carbohydrate Metabolism (drug effects)
• Chlamydia trachomatis (drug effects, 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)