A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/00303facf7d845949d710878fb025781
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spelling	oai:doaj.org-article:00303facf7d845949d710878fb0257812021-11-15T15:41:19ZA 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>10.1128/mBio.02304-142150-7511https://doaj.org/article/00303facf7d845949d710878fb0257812015-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02304-14https://doaj.org/toc/2150-7511ABSTRACT 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.Patrik EngströmK. Syam KrishnanBidong D. NgyuenErik ChorellJohan NormarkJim SilverRobert J. BastidasMatthew D. WelchScott J. HultgrenHans Wolf-WatzRaphael H. ValdiviaFredrik AlmqvistSven BergströmAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 1 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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 A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>
description	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.
format	article
author	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
author_facet	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
author_sort	Patrik Engström
title	A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>
title_short	A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>
title_full	A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>
title_fullStr	A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>
title_full_unstemmed	A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>
title_sort	2-pyridone-amide inhibitor targets the glucose metabolism pathway of <named-content content-type="genus-species">chlamydia trachomatis</named-content>
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/00303facf7d845949d710878fb025781
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A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of <named-content content-type="genus-species">Chlamydia trachomatis</named-content>

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