Metformin in tuberculosis: beyond control of hyperglycemia

Oglesby, William; Kara, Ali M.; Granados, Hector; Cervantes, Jorge

doi:10.1007/s15010-019-01322-5

Cited by 19 publications

(13 citation statements)

References 44 publications

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“…Repurposing existing drugs as supplemental agents in tandem with existing tuberculosis treatments may hold particular promise. For example, metformin, a drug commonly prescribed to type 2 diabetics, is an insulin sensitizer which targets complex I of the electron transport chain (El-Mir et al, 2000;Owen et al, 2000) and has been proposed as a supplementary therapy for Mtb which targets host metabolism (Oglesby et al, 2019). Epidemiological evidence has indicated that metformin both lowers the risk of developing active tuberculosis and lowers the associated mortality rate (Tseng, 2018;Zhang and He, 2020) while it has been shown to improve mycobacterial containment and reduce pulmonary pathology in a murine model of Mtb infection (Singhal et al, 2014), acting through multiple mechanisms centered around cellular metabolism including mitochondrial ROS generation (Lachmandas et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

An Army Marches on Its Stomach: Metabolic Intermediates as Antimicrobial Mediators in Mycobacterium tuberculosis Infection

Hackett

Sheedy

2020

Front. Cell. Infect. Microbiol.

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The cells of the immune system are reliant on their metabolic state to launch effective responses to combat mycobacterial infections. The bioenergetic profile of the cell determines the molecular fuels and metabolites available to the host, as well as to the bacterial invader. How cells utilize the nutrients in their microenvironment-including glucose, lipids and amino acids-to sustain their functions and produce antimicrobial metabolites, and how mycobacteria exploit this to evade the immune system is of great interest. Changes in flux through metabolic pathways alters the intermediate metabolites present. These intermediates are beginning to be recognized as key modulators of immune signaling as well as direct antimicrobial effectors, and their impact on tuberculosis infection is becoming apparent. A better understanding of how metabolism impacts immunity to Mycobacterium tuberculosis and how it is regulated and thus can be manipulated will open the potential for novel therapeutic interventions and vaccination strategies.

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Section: Resultsmentioning

confidence: 99%

An Army Marches on Its Stomach: Metabolic Intermediates as Antimicrobial Mediators in Mycobacterium tuberculosis Infection

Hackett

Sheedy

2020

Front. Cell. Infect. Microbiol.

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“…Other drugs such as metformin, a biguanide that is used extensively in the treatment of type 2 diabetes mellitus (T2DM) have recently been explored as HDTs for TB. Metformin functions in part as an inhibitor of complex I of the electron transport chain and has been shown to restrict intracellular Mtb growth, induce mitochondrial reactive oxygen species production, reduce TB pathology, inflammatory cytokine expression, and decrease the risk of developing active TB in patients with T2DM (Lin et al, 2018;Lachmandas et al, 2019;Oglesby et al, 2019;Yew et al, 2019;Abinaya et al, 2020;Rodriguez-Carlos et al, 2020). Additionally, ours and other laboratories have recently demonstrated that metformin improves clinical disease outcomes in animal models chronically infected with Mtb.…”

Section: Rise Of Host-directed Therapeutic Strategies To Combat Tbmentioning

confidence: 87%

“…MCT1 knockdown is more effective under hypoxic conditions, resulting in larger decreases in lactate levels, cell biomass, cell invasion, and drastic reduction in breast cancer growth, and treatment with metformin could increase the response/efficacy of the MCT1 inhibition (Morais-Santos et al, 2015). The research combining MCT inhibition and biguanides is of interest for TB therapy, as metformin has been actively explored as a HDT (Lin et al, 2018;Lachmandas et al, 2019;Oglesby et al, 2019;Yew et al, 2019;Abinaya et al, 2020;Frenkel et al, 2020;Rodriguez-Carlos et al, 2020). However, inhibiting MCTs has yet to be explored in the context of Mtb infection.…”

Section: Lactate Shuttling and Metabolism As A Therapeutic Targetmentioning

confidence: 99%

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

Kiran

Basaraba

2021

Front. Cell. Infect. Microbiol.

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Infection with Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.

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“…The antibacterial activity of metformin also attracted the attention of scientists as an adjuvant in tuberculosis (TB) treatment regimens[ 173 ]. Meta-analysis studies revealed reduced mortality rates and improved treatment outcomes in diabetic patients subjected to anti-TB regimen combined with metformin as anti-diabetic drug, also metformin administration was linked to reduced risk of TB disease among diabetics[ 174 , 175 ].…”

Section: Biguanide (Metformin)mentioning

confidence: 99%

Anti-diabetics and antimicrobials: Harmony of mutual interplay

Hegazy¹,

Rajab²,

Lila³

et al. 2021

WJD

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Diabetes is one of the four major non-communicable diseases, and appointed by the world health organization as the seventh leading cause of death worldwide. The scientists have turned over every rock in the corners of medical sciences in order to come up with better understanding and hence more effective treatments of diabetes. The continuous research on the subject has elucidated the role of immune disorders and inflammation as definitive factors in the trajectory of diabetes, assuring that blood glucose adjustments would result in a relief in the systemic stress leading to minimizing inflammation. On a parallel basis, microbial infections usually take advantage of immunity disorders and propagate creating a pro-inflammatory environment, all of which can be reversed by antimicrobial treatment. Standing at the crossroads between diabetes, immunity and infection, we aim in this review at projecting the interplay between immunity and diabetes, shedding the light on the overlapping playgrounds for the activity of some antimicrobial and anti-diabetic agents. Furthermore, we focused on the anti-diabetic drugs that can confer antimicrobial or anti-virulence activities.

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Metformin in tuberculosis: beyond control of hyperglycemia

Cited by 19 publications

References 44 publications

An Army Marches on Its Stomach: Metabolic Intermediates as Antimicrobial Mediators in Mycobacterium tuberculosis Infection

An Army Marches on Its Stomach: Metabolic Intermediates as Antimicrobial Mediators in Mycobacterium tuberculosis Infection

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

Anti-diabetics and antimicrobials: Harmony of mutual interplay

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