Iron limitation in M. tuberculosis has broad impact on central carbon metabolism

Theriault, Monique E.; Pisu, Davide; Wilburn, Kaley M; Lê-Bury, Gabrielle; McNamara, Case W.; Petrassi, H. Michael; Love, Melissa S.; Rock, Jeremy M.; VanderVen, Brian C.; Russell, David G.

doi:10.1038/s42003-022-03650-z

Cited by 17 publications

(23 citation statements)

References 58 publications

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“…Cholesterol is a vital nutrient for Mtb in vivo (Pandey & Sassetti, 2008), and given the synergistic response of Mtb to acidic pH and Cl − (Tan et al, 2013), we anticipate that similar cross‐regulation of the Mtb acidic pH regulon by the presence of cholesterol is also likely to occur, and studies pursuing this new facet of Mtb biology are in progress. Of note, it has also been reported that the growth of Mtb in acidic pH is improved in the presence of cholesterol or even‐chain fatty acids (Baker et al, 2014; Gouzy et al, 2021), and iron limitation results in upregulated expression of Mtb cholesterol utilization genes (Kurthkoti et al, 2017; Theriault et al, 2022). Together, these findings indicate the different relationships that can exist between bacterial metabolism and environmental cue response, and future studies probing this complex aspect will undoubtedly reveal new relationships critical for bacterial adaptation to its host.…”

Section: Coordination Of Bacterial Environmental Response With Its Me...mentioning

confidence: 99%

Shining a light on bacterial environmental cue integration and its relation to metabolism

Chen

Quirk

Tan

2023

Molecular Microbiology

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The ability of a bacterium to successfully colonize its host is dependent on proper adaptation to its local environment. Environmental cues are diverse in nature, ranging from ions to bacterial-produced signals, and to host immune responses that can also be exploited by the bacteria as cues. Simultaneously, bacterial metabolism must be matched to the carbon and nitrogen sources available at a given time and location.While initial characterization of a bacterium's response to a given environmental cue or its ability to utilize a particular carbon/nitrogen source requires study of the signal in question in isolation, actual infection poses a situation where multiple signals are present concurrently. This perspective focuses on the untapped potential in uncovering and understanding how bacteria integrate their response to multiple concurrent environmental cues, and in elucidating the possible intrinsic coordination of bacterial environmental response with its metabolism.

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Section: Coordination Of Bacterial Environmental Response With Its Me...mentioning

confidence: 99%

Shining a light on bacterial environmental cue integration and its relation to metabolism

Chen

Quirk

Tan

2023

Molecular Microbiology

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“…However, a recent macrophage infection drug screen demonstrated that one of the hit compounds limited Mtb’s access to iron by acting as an iron chelator. Mtb also has a greater dependency on iron when cultured with cholesterol as the sole carbon source, linking iron uptake and cholesterol metabolism ( Theriault et al., 2022 ). Another recent study demonstrated that iron levels play a role in modulating transcriptional responses to growth arrest when Mtb transition from exponential growth to stationary phase ( Alebouyeh et al., 2022 ).…”

Section: Lesion Microenvironments Give Rise To Non-replication and Su...mentioning

confidence: 99%

Tools to develop antibiotic combinations that target drug tolerance in Mycobacterium tuberculosis

Greenstein

Aldridge²

2023

Front. Cell. Infect. Microbiol.

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Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of Mycobacterium tuberculosis to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.

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“…Additionally, the effect of iron limitation on the survival ability of Mtb has received less attention. 15,16 In this study, we attempted to generate evidence of the pivotal role played by host iron in Mtb survival and how manipulating iron availability through chemical agents, such as iron chelators, may impact Mtb clearance in both in-vitro and in vivo settings.…”

Section: Ifnmentioning

confidence: 99%

Deferoxamine as adjunct therapeutics for tuberculosis

Kaushik

Sahu

Mohapatra

et al. 2023

Preprint

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Iron is a critical element used for survival of both host and pathogens. Tuberculosis patients show dysregulated iron metabolism and provide an opportunity for developing host directed therapeutics. In this study, C57BL/6 mice supplemented with ferric carboxymaltose and controls were aerosol infected with 100-120 CFU of the H37Rv strain of Mycobacterium tuberculosis. A subgroup of mice received deferoxamine (DFO) with or without isoniazid and rifampicin. The iron supplemented C57BL/6 mice showed higher tissue mycobacterial burden at 2 weeks of post infection. The efficacy of isoniazid and rifampicin was compromised in iron supplemented C57BL/6 mice. Iron chelation by deferoxamine (DFO) alone for a month significantly reduced the tissue mycobacterial burden but was less effective in the iron-supplemented group. DFO as an adjunct to isoniazid and rifampicin cleared the tissue mycobacteria more efficiently. Currently, DFO is used for treating acute iron poisoning and iron overloaded thalassemic patients and holds promise as an adjunct therapeutic agent for TB.

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Iron limitation in M. tuberculosis has broad impact on central carbon metabolism

Cited by 17 publications

References 58 publications

Shining a light on bacterial environmental cue integration and its relation to metabolism

Shining a light on bacterial environmental cue integration and its relation to metabolism

Tools to develop antibiotic combinations that target drug tolerance in Mycobacterium tuberculosis

Deferoxamine as adjunct therapeutics for tuberculosis

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