Combined Human Genome-wide RNAi and Metabolite Analyses Identify IMPDH as a Host-Directed Target against Chlamydia Infection

Cell Host Microbe. 2018 May 9;23(5):661-671.e8. doi: 10.1016/j.chom.2018.04.002. Epub 2018 Apr 26.


Chlamydia trachomatis (Ctr) accounts for >130 million human infections annually. Since chronic Ctr infections are extremely difficult to treat, there is an urgent need for more effective therapeutics. As an obligate intracellular bacterium, Ctr strictly depends on the functional contribution of the host cell. Here, we combined a human genome-wide RNA interference screen with metabolic profiling to obtain detailed understanding of changes in the infected cell and identify druggable pathways essential for Ctr growth. We demonstrate that Ctr shifts the host metabolism toward aerobic glycolysis, consistent with increased biomass requirement. We identify key regulator complexes of glucose and nucleotide metabolism that govern Ctr infection processes. Pharmacological targeting of inosine-5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, efficiently inhibits Ctr growth both in vitro and in vivo. These results highlight the potency of genome-scale functional screening for the discovery of drug targets against bacterial infections.

Keywords: Chlamydia trachomatis; IMPDH; MMF; RNAi screen; Warburg effect; metabolomics screen; nucleotide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Chlamydia Infections / metabolism*
  • Chlamydia Infections / pathology
  • Chlamydia trachomatis / growth & development
  • Chlamydia trachomatis / metabolism*
  • Chlamydia trachomatis / pathogenicity
  • Citric Acid Cycle
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics
  • Energy Metabolism
  • Female
  • Genome, Human*
  • Glucose / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions / genetics*
  • Host-Pathogen Interactions / physiology*
  • Humans
  • IMP Dehydrogenase / genetics*
  • IMP Dehydrogenase / metabolism*
  • Lung / microbiology
  • Lung / pathology
  • Male
  • Metabolic Networks and Pathways / genetics
  • Metabolic Networks and Pathways / physiology
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Models, Animal
  • NIH 3T3 Cells
  • Nucleotides / metabolism
  • RNA Interference*


  • Nucleotides
  • IMP Dehydrogenase
  • Glucose