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

2018; Cell Press; Volume: 23; Issue: 5 Linguagem: Inglês

10.1016/j.chom.2018.04.002

1934-6069

Marion Rother, Erik Gonzalez, Ana Rita Teixeira da Costa, Lea Wask, Isabella Gravenstein, Matteo Pardo, Matthias Pietzke, Rajendra Kumar Gurumurthy, Jörg Angermann, Robert Laudeley, Silke Glage, Michaël Meyer, Cindrilla Chumduri, Stefan Kempa, Klaus Dinkel, Anke Unger, Bert Klebl, Andreas Klos, Thomas F. Meyer,

Cervical Cancer and HPV Research

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.