Improved plaque assay identifies a novel anti-Chlamydia ceramide derivative with altered intracellular localization

Antimicrob Agents Chemother. 2014 Sep;58(9):5537-46. doi: 10.1128/AAC.03457-14. Epub 2014 Jul 7.

Abstract

Chlamydia trachomatis is a medically important human pathogen causing different diseases, including trachoma, the leading cause of preventable blindness in developing countries, and sexually transmitted infections that can lead to infertility and ectopic pregnancies. There is no vaccine against C. trachomatis at present. Broad-spectrum antibiotics are used as standard therapy to treat the infection but have unwanted side effects, such as inducing persistent or recurring infections and affecting the host microbiome, necessitating the development of novel anti-Chlamydia therapies. Here, we describe the establishment of a robust, fast, and simple plaque assay using liquid overlay medium (LOM) for the identification of anti-Chlamydia compounds. Using the LOM plaque assay, we identified nitrobenzoxadiazole (NBD)-labeled 1-O-methyl-ceramide-C16 as a compound that efficiently inhibits C. trachomatis replication without affecting the viability of the host cell. Further detailed analyses indicate that 1-O-methyl-NBD-ceramide-C16 acts outside the inclusion. Thereby, 1-O-methyl-NBD-ceramide-C16 represents a lead compound for the development of novel anti-Chlamydia drugs and furthermore constitutes an agent to illuminate sphingolipid trafficking pathways in Chlamydia infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Biological Transport
  • Cell Line, Tumor
  • Ceramides / pharmacology*
  • Ceramides / therapeutic use
  • Chlamydia Infections / drug therapy
  • Chlamydia trachomatis / drug effects*
  • Clinical Laboratory Techniques / methods*
  • Drug Discovery / methods
  • HeLa Cells
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Sphingolipids / metabolism

Substances

  • Anti-Bacterial Agents
  • Ceramides
  • Sphingolipids