Combined human genome-wide RNAi and metabolite analyses identify IMPDH as a host-directed target against Chlamydia infection

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-50-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.