Structural homology between mammalian 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) an InhA from Mycobacterium tuberculosis point to dehydroepiandrosterone (DHEA) as a potential co-adjuvant treatment in diabetes-tuberculosis co-morbidity

HERNANDEZ BUSTAMANTE, ISRAEL; SANTANDER PLANTAMURA, YANINA; REYES-CHAPARRO, ANDRÉS; MATA-ESPINOSA, DULCE; BINI, ESTELA I.; HERNÁNDEZ-PANDO, ROGELIO; CARRANZA, ANDREA

Congreso; V International Congress in Traslational Medicine; 2021

Type 2 diabetes mellitus (T2DM) is estimated to affect half a billion people worldwide and is associated with a high fat diet (HFD) that induces obesity and immunosuppression. Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), remains a major cause of morbidity and mortality in developing countries. People with T2DM are prone to infection with Mtb. The anti-inflammatory glucocorticoids (GC) are secreted by the adrenal cortex but are regulated by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which catalyzes the activation of cortisone to cortisol (11-dehydrocorticosterone to corticosterone in rodents) into the endoplasmic reticulum of the extra-adrenal cells. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) counteracts GC signaling on pro-inflammatory cytokine production due to inhibition of the 11beta-HSD1. During the chronic phase of T2DM-TB comorbidity, a high extra-adrenal activation of GC by 11beta-HSD1 has been associated with insulin resistance and suppression of Th1 response, evidenced by cortisol/DHEA imbalance. In previous work, we demonstrated in an experimental TB/T2DM comorbidity induced by HFD and Mtb infection that the treatment with DHEA decreased circulating GC and lung 11-beta-HSD1 expression lowering lung bacillary loads and pneumonia in comparison with TB mice. We explored 1) if DHEA administration can modify the lung inflammation in HFD mice; 2) the microbicide effect of DHEA on Mtb survival; 3) analyzed the structural homology between InhA (an essential Mtb enzyme) and 11-beta-HSD1 and 4) the interaction InhA -DHEA by docking analyses. Our results suggest that HFD mice have an increased expression of pro-inflammatory cytokines (TNF-a, IL-1b and IL-6) in the lungs with an increase of circulating corticosterone with the finality to inhibit lung inflammation. The administration of DHEA to HSD mice elevates the concentration of cytokines and reduces corticosterone activation by 11-beta-HSD1. The microbicide effect of DHEA on Mtb was supported by the characterization of the structural homology studies between 11beta-HSD1 and InhA enzyme and molecular docking between DHEA and InhA. This double function of DHEA treatment inhibiting mammalian 11beta-HSD1 and bacterial InhA point to suggest a rational drug design based on DHEA structure that could be a co-adjuvant therapy for T2DM and TB comorbidity.