Recombinant M. Tuberculosis p60-Related Protein (Rv0024) [His]

Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8(+)CXCR3(+) T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8(+) T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8(+) T cells from Cxcr3(-/-) mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8(+) T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection. Metformin is an anti-diabetic drug that has shown promise to reduce M. tuberculosis susceptibility. Here the authors show that this effect is a result of metformin-mediated activation of anti-mycobacterial memory-like antigen-inexperienced CD8(+)CXCR3(+) T cells, an effect that also boosts response to BCG vaccination.

Background: A major focus of tuberculosis drug discovery is aimed at the development of novel antibiotics with activity against drug-resistant strains of Mycobacterium tuberculosis. Results: We have synthesized ten isoniazid derivatives and investigated for antibacterial activity toward M. tuberculosis H37Rv and isoniazid-resistant strain SRI 1369. It was revealed that only one compound, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide (1), is active toward isoniazid-resistant strain with minimum inhibitory concentration value of 0.14 mu M. This compound is not cytotoxic toward human liver cells (HepG2; IC50 >100 mu M), demonstrates good permeability in Caco-2 cells. Accordingly to the results of plasma protein binding assay, unbound fraction of compound 1, which potentially exhibits pharmacologic effects, is 57.9%. Conclusion: Therefore, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide is a promising compound for further preclinical studies.