European Conference on Mathematical and Theoretical Biology (ECMTB 2026)

Targeting metabolic fluxes to prevent drug tolerance in Mycobacterium Tuberculosis under host-derived stress

15 Jul 2026, 08:50

20m

11.02 - HS (University of Graz)

Contributed Talk Systems Biology and Biochemical Networks Contributed Talks

Speaker

Tanishk Patodi (Indian Institute of Science, Bengaluru, India)

Description

Tuberculosis remains a major cause of death among infectious diseases despite the availability of multiple antibiotics against the causative agent Mycobacterium Tuberculosis (Mtb). Heterogeneity in Mtb population upon host infection prevents clearance of Mtb under antibiotic exposure. Mtb is known to differ in its redox environment, and the subpopulation with a reduced (oxidised) cytoplasmic environment is more tolerant (sensitive) to drugs. Handling such heterogeneity necessitates a protracted treatment and increases the chances of relapse. Cues from macrophages are known to influence the emergence of this population heterogeneity; however, the mechanisms underlying this process remain unclear.
In this study, we employed a genome-scale metabolic model of Mtb, iEK1011_2.0, to identify how individual bacilli reroute their metabolic pathways crucial for Mtb to become drug-tolerant under host-derived stress. We derived context-specific models for phenotype-specific sub-populations (i.e., tolerant and sensitive populations) using RNA-seq data and employed gene knockout strategies to target the metabolic changes responsible for the phenotypic transitions. Our systems-level analysis reveals metabolic changes that contribute to the spontaneous emergence of phenotypic heterogeneity in Mtb within infected macrophages and serves as a platform to identify novel potent interventional strategies.

Bibliography

@article{lopez-agudelo_systematic_2020,
title = {A systematic evaluation of {Mycobacterium} tuberculosis {Genome}-{Scale} {Metabolic} {Networks}},
volume = {16},
issn = {1553-7358},
url = {https://dx.plos.org/10.1371/journal.pcbi.1007533},
doi = {10.1371/journal.pcbi.1007533},
language = {en},
number = {6},
urldate = {2026-01-20},
journal = {PLOS Computational Biology},
author = {López-Agudelo, Víctor A. and Mendum, Tom A. and Laing, Emma and Wu, HuiHai and Baena, Andres and Barrera, Luis F. and Beste, Dany J. V. and Rios-Estepa, Rigoberto},
editor = {Wallqvist, Anders},
month = jun,
year = {2020},
pages = {e1007533},
}

@article{mishra_targeting_2019,
title = {Targeting redox heterogeneity to counteract drug tolerance in replicating \textit{{Mycobacterium} tuberculosis}},
volume = {11},
issn = {1946-6234, 1946-6242},
url = {https://www.science.org/doi/10.1126/scitranslmed.aaw6635},
doi = {10.1126/scitranslmed.aaw6635},
abstract = {Chloroquine resets the redox physiology of
Mycobacterium tuberculosis
to potentiate the efficacy of antibiotics in vivo.

      , 
        Antibiotic redox-based redux

          Phagosomal pH and redox heterogeneity in
          Mycobacterium tuberculosis
          (
          Mtb
          ) can promote tolerance of the bacterium to antibiotics. Mishra
          et al.
          found that the approved antimalarial drug chloroquine inhibited this acidification and resulted in altered redox metabolism and improved susceptibility of
          Mtb
          to first-line antituberculosis drugs, particularly isoniazid, in infected macrophages in vitro. Coadministration of chloroquine improved isoniazid treatment outcomes in both mouse and guinea pig models of
          Mtb
          infection. This work suggests the repurposing of chloroquine to potentiate and possibly shorten antibiotic treatment of tuberculosis.

      ,

          The capacity of
          Mycobacterium tuberculosis
          (
          Mtb
          ) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in
          Mtb
          populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of
          Mtb
          to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H
          2
          S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when
          Mtb
          infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant
          Mtb
          , ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (
          C
          max
          and AUC
          last
          ) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating
          Mtb
          and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.},
language = {en},
number = {518},
urldate = {2026-01-20},
journal = {Science Translational Medicine},
author = {Mishra, Richa and Kohli, Sakshi and Malhotra, Nitish and Bandyopadhyay, Parijat and Mehta, Mansi and Munshi, MohamedHusen and Adiga, Vasista and Ahuja, Vijay Kamal and Shandil, Radha K. and Rajmani, Raju S. and Seshasayee, Aswin Sai Narain and Singh, Amit},
month = nov,
year = {2019},
pages = {eaaw6635},

}