RESUMEN
Mycobacteria tuberculosis (M.tb) the causative agent for tuberculosis has been accredited for a high rate of morbidity and mortality worldwide. The rise in MDR and XDR cases has further created new obstacles in achieving the "End TB Strategy", which is aimed for 2035. In this article, we have demonstrated the potential of sphingosine-1-phosphate (S1P) analogs in providing an anti-mycobacterial effector response by altering macrophage polarity into M1. Among S1PR1 and S1PR3 analogs, S1PR2 analogs proficiently favor selective polarization of infected human macrophages into M1 phenotypes, marked by increased expression of M1 markers and decreased M2 markers. Furthermore, S1PR1-3 analogs treated macrophages were also able to decrease the secretion of anti-inflammatory cytokine IL-10 and can induce NO secretion in infected macrophages. Lastly, only S1PR2-3 analogs were able to restrict the growth of mycobacteria in human macrophages. Taken together our study reflects the potential of S1PR2-3 analogs in providing host defenses following mycobacterial infection by favoring M1 macrophage polarization.
RESUMEN
This study examined the hypothesis that there is an impairment of macrophageal function in spinal TB. We examined macrophageal functions in spinal TB patients. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of five spinal TB patients and five healthy persons as control. The isolated monocytes were cultured with stimulation of macrophage colony-stimulating factor (M-CSF) for seven days for maturation. The phagocytic ability of the macrophages derived from monocytes was measured. Also, nitric oxide (NO), myeloperoxidase (MPO), beta-glucuronide, and acid phosphatase activity was investigated. We found that the monocytes collected from patient PBMCs were significantly fewer than those of the control group (2992.103 vs. 6474.103 (cells/mL)). There were also fewer macrophages that had adhered to sheep red blood cells (SRBC) (598.103 vs. 264.103 (cells/mL)). However, NO production (2346 vs. 325.17 (µmol/gram of protein)), and the MPO (570.7 vs. 17.4 (unit/mg), beta-glucuronide (0.149 vs. 0.123 (µmol/hour/100 mg of protein)), and acid phosphatase activities (1776.9 vs. 287.9 (µmol/hour/100 mg of protein)) of the macrophages in the spinal TB group were markedly higher than in the healthy group. Despite the low adhesion to foreign bodies, the intracellular processing of TB macrophages, including oxidative activity and lysosome function, was significantly high. These results suggested the impairment of macrophageal function in spinal TB. Possibly, there is a dominance of innate non-specific immunity in spinal TB infection.
RESUMEN
Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.
Asunto(s)
Antituberculosos/farmacología , Diarilquinolinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Diarilquinolinas/síntesis química , Diarilquinolinas/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.