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Sci Adv. 2019 Mar 20;5(3):eaav2104. doi: 10.1126/sciadv.aav2104. eCollection 2019 Mar.

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

Author information

1
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Medical Department, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
3
Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
4
Molecular Discovery Research, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
5
Biostatistics and Bioinformatics Unit, IMDEA Food Institute, Madrid, Spain.
6
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
7
Department of Molecular Microbiology and Immunology, Keck School of Medicine of USC, Los Angeles, CA, USA.
8
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
9
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Abstract

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

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