TY - JOUR
T1 - Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence
AU - Dutta, Noton
AU - Klinkenberg, Lee
AU - Vazquez, Maria Jesus
AU - Segura-Carro, Delfina
AU - Colmenarejo, Gonzalo
AU - Ramon, Fernando
AU - Rodriguez-Miquel, Beatriz
AU - Mata-Cantero, Lydia
AU - Francisco, Esther Porras De
AU - Chuang, Yu Min
AU - Rubin, Harvey
AU - Lee, Jae Jin
AU - Eoh, Hyungjin
AU - Bader, Joel S.
AU - Perez-Herran, Esther
AU - Mendoza-Losana, Alfonso
AU - Karakousis, Petros C.
N1 - Funding Information:
We would like to acknowledge Metabolon Inc. for generation of the metabolomics data. This work was supported by R01AI083125, R21AI122922, and R21AI114507A to P.C.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063322846&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063322846&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aav2104
DO - 10.1126/sciadv.aav2104
M3 - Article
C2 - 30906866
AN - SCOPUS:85063322846
SN - 2375-2548
VL - 5
JO - Science Advances
JF - Science Advances
IS - 3
M1 - eaav2104
ER -