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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Engström, P; Krishnan, KS; Ngyuen, BD; Chorell, E; Normark, J; Silver, J; Bastidas, RJ; Welch, MD; Hultgren, SJ; Wolf-Watz, H; Valdivia, RH; Almqvist, F; Bergström, S

Published Date

  • December 30, 2014

Published In

Volume / Issue

  • 6 / 1

Start / End Page

  • e02304 - e02314

PubMed ID

  • 25550323

Pubmed Central ID

  • 25550323

Electronic International Standard Serial Number (EISSN)

  • 2150-7511

International Standard Serial Number (ISSN)

  • 2150-7511

Digital Object Identifier (DOI)

  • 10.1128/mBio.02304-14

Language

  • eng