Abstract
PA-824 is a novel bicyclic nitroimidazole anti-tuberculosis (TB) drug. Cordyceps sinensis (Berk.) Sacc. (CS) was proven to be a good immunomodulatory compound. This research aimed to investigate the effect of CS on PA-824 in Mycobacterium tuberculosis (M.tb) infected mice (female CBA/J mice, 6 to 8 weeks of age and 20±2 g of weight). Mice were randomly assigned to 4 groups: PA-824, CS, PA-824+CS, and control. To verify the effect of PA-824 and CS on M.tb, after drug administration, mice lungs were harvested and bacterial colony formations were measured. Cells were isolated from infected lungs and spleens to analyze the percentage of CD4+ T cells (CD11a positive). Lung cells were cultured to detect the secretion of interferon-γ (IFN-γ) and interleukin-10 (IL-10) by ELISA. IFN-γ and IL-10 double-positive CD4+ cells in peripheral blood were measured by flow cytometry. The expression levels of IL-2 and IL-10 in mice lungs were analyzed by real-time PCR and western blot. Results showed that PA-824 combined with CS led to the lowest lung colony-forming units (CFU) counts among treated groups. Furthermore, this beneficial outcome might be associated with the decreased CD11a on CD4+ cells in mice lungs and spleens. Moreover, the suppressed secretion of IFN-γ and IL-10, and IL-10 expressions, as well as the decreased IFN-γ and IL-10 double-positive CD4+ cells in blood, could also be associated with the positive effect. However, no significant effect on IL-2 production was found. The combination of PA-824 and CS had more effective bacteriostatic and immunomodulatory effects on M.tb infected mice than PA-824 alone. In conclusion, CS has the potential to be an effective adjuvant in TB treatment.
Highlights
Tuberculosis (TB) is still a major global health problem even with the slightly decreasing incidence in recent years [1]
After 8 weeks, lung colony-forming units (CFU) counts in mice lungs treated with PA-824 alone, Cordyceps sinensis (Berk.) Sacc. (CS) alone and PA-824+CS were significantly decreased compared to the control group (Po0.05 or Po0.01)
Analysis of the expressions of CD11a on CD4+ cells in the spleen of treated mice showed the similar result (Po0.05 or Po0.01, Figure 2B). These results suggested that PA-824 treatment decreased CD11a expressions on CD4+ T cells in lung and spleen and CS enhanced the efficacy of PA-824
Summary
Tuberculosis (TB) is still a major global health problem even with the slightly decreasing incidence in recent years [1]. The crucial point of TB treatment regimen is security and practicability. A novel drug should be able to interact with other drugs freely, and without competing with or causing resistance of current drugs, especially multidrug-resistance. The nitroimidazooxazine PA-824 represents a new class of anti-tubercular drugs [2]. PA-824 is one of the novel bicyclic nitroimidazole drugs for TB treatment that has already been in phase II clinical trials, and the other one is OPC-67683 [3]. PA-824 has potent activity against Mycobacterium tuberculosis (M.tb) in vitro, and does not demonstrate cross-resistance to a variety of commonly used anti-TB drugs [4,5]. Antibacterial activity of PA-824 to M.tb and multidrug resistance were evaluated, the exact mechanism is not well known [6,7]
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