Metformin as adjunct antituberculosis therapy

Singhal, Amit; Liu, Jie; Kumar, Pavanish; Hong, Gan Suay; Leow, Melvin Khee–Shing; Paleja, Bhairav; Tsenova, Liana; Kurepina, Natalia; Chen, Jinmiao; Zolezzi, Francesca; Kreiswirth, Barry N.; Poidinger, Michael; Chee, C. B. E.; Kaplan, Gilla; Wang, Yee Tang; Libero, Gennaro De

doi:10.1126/scitranslmed.3009885

Cited by 419 publications

(571 citation statements)

References 51 publications

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“…Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6). In another retrospective study, Srujitha et al showed that MetF use was associated with a 3.9-fold reduction in TB incidence among patients with DM (7).…”

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confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the firstline regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.KEYWORDS Mycobacterium tuberculosis, metformin, standard first-line regimen, BALB/c, bactericidal, sterilizing, host-directed therapy, relapse, cure, Denver regimen H ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1-5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6). In another retrospective study, Srujitha et al. showed that MetF use was associated with a 3.9-fold reduction in TB incidence among patients with DM (7). Based on these findings, we hypothesized that MetF adjunctive therapy would enhance the bactericidal and sterilizing activities of the standard first-line treatment (8, 9) against chronic TB infection in mice and shorten the duration of curative treatment as assessed by microbiological relapse.All animal-related procedures were approved by the Johns Hopkins University (JHU) School of Medicine Animal Care and Use Committee. A total of 170 female BALB/c mice aged 4 to 6 weeks (Charles River Labs, Wilmington, MA) were aerosol infected with Mycobacterium tuberculosis H37Rv (JHU) using the inhalation exposure system (GlasCol, Terre Haute, IN) calibrated to deliver ϳ10 2 CFU per mouse lung in two consecutive runs. After aerosol infection, the mice were randomized into the two treatment groups. Six weeks postinfection, the mice were treated daily (5 days/week) via esophageal cannulation with human-equivalent doses of rifampin (10 mg/kg), isoniazid (10 mg/kg), pyrazinamide (150 mg/kg), and ethambutol (100 mg/kg) (RHZE) with or without MetF (250 mg/kg) for up to 6 months (2, 10, 11). For the first 2 months of treatment, the mice received RHZE and, for the remaining 4 months, only rifampin and isoniazid (RH) to mirror the first-line regimen in humans. The rifampin dose preceded that of the other drugs by at least 1 h to prevent pharmacokinetic antagonism (12, 13). The dose of MetF (6) and is estimated (14) to be equivalent to 25 mg/kg in humans (15), which is well tolerated (15, 16). Groups of 5 mice were sacrificed on the day after infection, on the day of treatment initi...

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confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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“…132 AMPK is activated by metformin, a type-2 diabetes drug, 133 that reduces bacterial burden and ameliorates lung pathology in mice and humans by enhancing autophagy and increasing ROS production. 92 Metformin adjunctive treatment however failed to improve sterilizing activity and TB relapsed in mice, with no significant effect being reported for culture conversion rates in diabetes mellitus patients with TB. 134 …”

Section: Kinase Modulatorsmentioning

confidence: 99%

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tiberi

Plessis

Walzl

et al. 2018

The Lancet Infectious Diseases

289

275

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Tuberculosis (TB) remains the top killer from an infectious globally causing an estimated 1.674.000 million deaths worldwide. In 2016, WHO estimates 600.000 cases of rifampicin-resistant TB of which 490.000 had multidrug-resistant (MDR) and less than half of them survive after receiving currently recommended WHO treatment regimens, illustrating weaknesses in current treatment approaches. We review progress and advances in the development of new and repurposed TB drugs, treatment trials and host-directed therapies. Updates are provided on phase 3 trials of the new compounds bedaquiline, delamanid, pretomanid; phase 2 trials of sutezolid, SQ-109, LCB01-0371, PBTZ-169; and five new drugs in phase 1 development. Approved or repurposed drugs undergoing further testing are rifampicin, rifapentine, clofazimine, and linezolid. Update on ongoing clinical trials, which aim to shorten TB treatment and improve treatment outcome is given. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR-TB, and five antimicrobial drug candidates are in phase 1 (Q203, TBI-166, OPC-167832, GSK 070, TBA-7371) and 5 in pre-clinical studies. Specific issues of safety and toxicity; drug-drug interactions; Therapeutic Drug Monitoring are reviewed. A wide range of candidate host-directed therapies (HDTs) and immune-based treatments are being investigated to accelerate the eradication of M.tb infection and for use as adjunctive therapy in shortening duration of treatment, preventing permanent lung injury and improving treatment outcomes of MDR-TB. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented.5

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“…In addition, a DDI study in rats involving berberine and metformin interactions reported an increased initial plasma concentration and AUC for metformin, and a decreased systemic clearance and volume of distribution were observed for metformin due to the inhibition of OCT1 and OCT2 by berberine (33). Another study suggested the use of metformin as an adjunctive therapy to improve the efficacy of anti-TB drugs (34), but the findings of the current in vitro study suggest that consideration is warranted before prescribing anti-TB drugs with metformin. Again, we must emphasize that the interactions of these anti-TB drugs with multidrug and toxin extrusion (MATE) transporters play a major role in the renal clearance of cations as does OCT2.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family

Parvez

Kaisar

Shin

et al. 2016

Antimicrob Agents Chemother

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b Twenty-two currently marketed antituberculosis drugs were comprehensively evaluated for their inhibitory effect on organic anionic transporter (OAT)-and organic cation transporter (OCT)-mediated uptake using stably transfected HEK293 cells in vitro. We observed moderate to strong inhibitory effects on OAT1-and OAT3-mediated para-aminohippurate (PAH) uptake and OCT1-and OCT2-mediated N-methyl-4-phenylpylidinium acetate (MPP ؉ ) uptake. Ciprofloxacin, linezolid, para-aminosalicylic acid (PAS), and rifampin were observed to have strong inhibitory effects, with the concentrations for a 50% inhibitory effect (IC 50 s) being 35.1, 31.1, 37.6, and 48.1 M, respectively, for OAT1 and >100, 21.9, 24.6, and 30.2 M, respectively, for OAT3. Similarly, pyrazinamide, rifabutin, and levofloxacin were observed to have inhibitory effects, with IC 50 values being 36.5, 42.7, and 30.3 M, respectively, for OCT1 and with the IC 50 value for PAS being 94.2 M for OCT2. In addition, we used zidovudine and metformin as clinically prescribed substrates of OATs and OCTs, respectively, and zidovudine and metformin uptake was also strongly inhibited by the antituberculosis drugs. Among the tested drugs, the highest drug-drug interaction (DDI) indexes were found for PAS, which were 9.3 to 13.9 for OAT1 and 12.0 to 17.7 for OAT3, and linezolid, which were 1.18 to 2.15 for OAT1 and 1.7 to 3.01 for OAT3. Similarly, the DDI indexes of pyrazinamide and levofloxacin were 0.57 and 0.30, respectively, for OCT1, and the DDI index of PAS was 3.8 for OCT2, suggesting a stronger possibility (DDI index value cutoff, >0.1) of in vivo DDIs. This is the first comprehensive report of the inhibitory potential of anti-TB drugs on OAT-and OCT-mediated uptake of prototype and clinically prescribed substrate drugs in vitro, providing an ability to predict DDIs between anti-TB drugs and other coprescribed drugs in clinical studies in vivo. So far, 400 human solute carrier family (SLC) transporter proteins have been identified as a superfamily and have been classified into 52 different subfamilies (1). The organic cation transporter (OCT; SLC22 subfamily) and organic anion transporter (OAT; SLC22 subfamily) families play a major role in the disposition and pharmacology of drug substances (2). Among these, organic cation transporter OCT1 (SLC22A1) appears to be highly expressed in the liver of all species and in many tissues, although intriguing differences between species have been noted. OCT1 expression is restricted to the basolateral membrane of proximal tubular cells, with the greatest expression being apparent in an early segment (segment S1) of superficial, midcortical, and juxtamedullary nephrons (3), whereas OCT2 (SLC22A2) is expressed in the kidney and appears to be restricted to the basolateral membrane of proximal tubular cells (4).The function of OCTs includes mediation of the transport of organic cations into or out of cells. Not all but many organic cations (of endogenous and exogenous origin) are substrates of OCTs. Endogenous organic cations includ...

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Metformin as adjunct antituberculosis therapy

Abstract: Metformin can be repurposed as host-directed therapy for tuberculosis.

Cited by 419 publications

References 51 publications

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family

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