Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence

摘要: The stringent response enables Mycobacterium tuberculosis (Mtb) to shut down its replication and metabolism under various stresses. Here we show that Mtb lacking the enzyme RelMtb was unable slow rate during nutrient starvation. Metabolomics analysis revealed nutrient-starved relMtb-deficient strain had increased similar of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability enter quiescence. Deficiency relMtb susceptibility mutant killing by isoniazid starvation lungs chronically infected mice. We screened a pharmaceutical library over 2 million compounds for inhibitors showed lead compound X9 able directly kill M. enhanced activity isoniazid. Inhibition is promising approach target persisters, potential shorten duration TB treatment.