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

Noton K. Dutta, Lee G. Klinkenberg, Maria Jesus Vazquez, Delfina Segura-Carro, Gonzalo Colmenarejo, Fernando Ramon, Beatriz Rodriguez-Miquel, Lydia Mata-Cantero, Esther Porras De Francisco, Yu Min Chuang, Harvey Rubin, Jae Jin Lee, Hyungjin Eoh, Joel S. Bader, Esther Perez-Herran, Alfonso Mendoza-Losana, Petros C. Karakousis

Research output: Contribution to journalArticle

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 Rel Mtb was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved rel Mtb -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 rel Mtb 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 Rel Mtb 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 Rel Mtb is a promising approach to target M. tuberculosis persisters, with the potential to shorten the duration of TB treatment.

Original languageEnglish (US)
Article numbereaav2104
JournalScience Advances
Volume5
Issue number3
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Physics and Astronomy (miscellaneous)
  • General

Cite this

Dutta, N. K., Klinkenberg, L. G., Vazquez, M. J., Segura-Carro, D., Colmenarejo, G., Ramon, F., Rodriguez-Miquel, B., Mata-Cantero, L., Francisco, E. P. D., Chuang, Y. M., Rubin, H., Lee, J. J., Eoh, H., Bader, J. S., Perez-Herran, E., Mendoza-Losana, A., & Karakousis, P. C. (2019). Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence. Science Advances, 5(3), [eaav2104]. https://doi.org/10.1126/sciadv.aav2104