Tuberculosis is an ancient disease that humanity struggled with for centuries and continues to struggle with. The bacteria Mycobacterium tuberculosis often infects the lungs through respiratory transmission and manifests itself through various symptoms, including cutaneous infections. Cutaneous tuberculosis (CTB) comprises about 1% to 1.5% of all extrapulmonary manifestations and is often accompanied by polymorphous lesions, including papules, nodules, plaques, ulcers, gummas, and verrucous lesions. CTB is most commonly observed in low-income, HIV, and immunosuppressed populations, similar to intrapulmonary manifestations. The main pathogen for CTB is M. tuberculosis but less commonly with M. bovis and BCG vaccine, and the modes of transmission are largely classified into exogenous and endogenous CTB. Current treatment options for CTB include oral therapy of antibiotic medications such as rifampicin, streptomycin, ethambutol, isoniazid, and pyrazinamide, which is occasionally combined with surgical intervention.

Glutathione (GSH) is an important intracellular antioxidant responsible for neutralizing reactive oxygen species (ROS). Our laboratory previously demonstrated that the oral administration of liposomal GSH improves immune function against mycobacterium infections in healthy patients along with patients with HIV and Type 2 diabetes. We aim to determine if the topical application of a glutathione–cyclodextrin nanoparticle complex (GSH-CD) confers a therapeutic effect against mycobacterium infections. In our study, healthy participants received either topical GSH-CD (n = 15) or placebo (n = 15) treatment. Subjects were sprayed four times twice a day for three days topically on the abdomen. Blood draws were collected prior to application, and at 1, 4, and 72 h post-initial topical application. GSH, malondialdehyde (MDA), and cytokine levels were assessed in the processed blood samples of study participants. Additionally, whole blood cultures from study participants were challenged with Mycobacterium avium (M. avium) infection in vitro to assess mycobacterium survival post-treatment. Topical GSH-CD treatment was observed to elevate GSH levels in peripheral blood mononuclear cells (PBMCs) and red blood cells and decrease MDA levels in PBMCs 72 h post-treatment. An increase in plasma IL-2, IFN-γ, IL-12p70, and TNF-α was observed at 72 h post-topical GSH-CD treatment. Enhanced mycobacterium clearance was observed at 4 h and 72 h post-topical GSH-CD treatment. Overall, topical GSH-CD treatment was associated with improved immune function against M. avium infection. The findings of this pilot study suggest GSH–cyclodextrin complex formulation can be used topically as a safe alternative mode of GSH delivery in the peripheral blood.

Mycobacterium avium complex (MAC) infections present significant therapeutic challenges due to their inherent antibiotic resistance, demanding innovative treatment approaches. This study investigated the antimicrobial and antioxidant potential of a novel compound, Fullerene Gallium Phosphonate (FGP), and compared its effects against a previously tested similar compound, Fullerene Disodium Phosphonate (FDSP). Results of experiments using MAC cultures and infected THP-1 macrophages treated with varying FGP and FDSP concentrations (1, 10, 100 µg/mL) revealed that FGP demonstrated greater efficacy than FDSP in reducing M. avium colony-forming units (CFU), achieving a nearly 3-fold reduction by day 8, compared to a 2-fold decrease with FDSP. In infected macrophages, FGP significantly decreased bacterial load at 1 and 10 µg/mL (p < 0.01). FGP also lowered oxidative stress, reflected by a significant reduction in malondialdehyde (MDA) levels on day 4 (p < 0.05) and decreased IL-6 (2-fold) and TNF-α levels (3-fold) by day 8, indicating both antimicrobial and anti-inflammatory effects. However, FGP paradoxically increased MAC burden at its highest concentration and showed no significant difference in efficacy of different concentrations. These findings suggest that FGP may serve as a promising candidate for antimycobacterial therapy with dual antibacterial and antioxidant effects. Further research is crucial to fully elucidate its mechanism of action and find the optimal therapeutic window.

Extrapulmonary tuberculosis (EPTB) accounts for approximately 17% of all Mycobacterium tuberculosis (M.tb) infections globally. Immunocompromised individuals, such as those with HIV infection or type 2 diabetes mellitus (T2DM), are at an increased risk for EPTB. Previous studies have demonstrated that patients with HIV and T2DM exhibit diminished synthesis of glutathione (GSH) synthesizing enzymes. In a murine model, we showed that the diethyl maleate (DEM)-induced depletion of GSH in the lungs led to increased M.tb burden and an impaired pulmonary granulomatous response to M.tb infection. However, the effects of GSH depletion during active EPTB in the liver and spleen have yet to be elucidated. In this study, we evaluated hepatic GSH and malondialdehyde (MDA) levels, as well as cytokine profiles, in untreated and DEM-treated M.tb-infected wild-type (WT) C57BL/6 mice. Additionally, we assessed hepatic and splenic M.tb burdens and tissue pathologies. DEM treatment resulted in a significant decrease in the levels of the reduced form of GSH and an increase in MDA, oxidized GSH, and interleukin (IL)-6 levels. Furthermore, DEM-induced GSH decrease was associated with decreased production of IL-12 and IL-17 and elevated production of interferon-gamma (IFN-γ), tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β. A significant increase in M.tb growth was detected in the liver and spleen in DEM-treated M.tb-infected mice. Large, disorganized lymphocyte infiltrates were detected in the hepatic tissues of DEM-treated mice. Overall, GSH diminishment impaired the granulomatous response to M.tb in the liver and exacerbated M.tb growth in both the liver and spleen. These findings provide critical insights into the immunomodulatory role of GSH in TB pathogenesis and suggest potential therapeutic avenues for the treatment of extrapulmonary M.tb infections.