The Search for New Agonists to P2X7R for Clinical Use: Tuberculosis as a Possible Target

Abstract

Treatment for tuberculosis is effective with the use of proper antibiotics, but the number of drug-resistant cases is increasing. Drug resistance occurred in 650,000 cases of the 20 million patients in treatment worldwide in 2011, which demonstrates the necessity of finding new therapeutic approaches. In this context, the search for new medicines and immunomodulators could help reduce the prevalence and incidence of multi-drug-resistant tuberculosis cases. Thus several preclinical studies demonstrate the involvement of the P2X7 receptor (P2X7R) in the control of Mycobacterium tuberculosis (MTB) infection. Adenosine triphosphate (ATP), a natural agonist for P2X7R, promotes MTB death and the induction of apoptosis in monocytes and macrophages infected with MTB via activation of P2X7R by extracellular ATP. In addition, P2X7R activation in the presence of ATP increases the expression of major histocompatibility complex (MHC) class II by macrophages infected with Mycobacterium bovis (BCG) or MTB, which contributes to the generation of the antimicrobial immune response via T cells. Nevertheless, one idea that seems overlooked by the “purinergic community” is the use of the high-conductance channel associated with P2X7R to increase the passage of hydrophilic drugs to the cytoplasm of cells that express the P2X7 pore, a potential method for a drug delivery system. In this work, we propose the use of P2X7 agonists in conjunction with low molecular weight anti-tuberculosis medicines for the treatment of multi-drug-resistant tuberculosis.

Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

“…In this review, we have discussed the complexity of this pathway where depending on the concentration used, the receptor or the enzyme involved, metabolites from the purinergic pathway can generate opposite effects. Members of the purinergic pathway represent now promising curative strategy for intracellular infections (Soares-Bezerra et al, 2015 ).…”

Purinergic Signalling: Therapeutic Developments

“…Over-expression of the ectonucleotidase, CD39, promotes bacteria-induced inflammation, mediated largely by P2X7R in mouse airways. It has been proposed that P2X7R agonists together with low molecular weight anti-tuberculosis medicines could be used to treat multi-drug-resistant tuberculosis (TB) ( Soares-Bezerra et al, 2015 ), although caution was advised as a polymorphism of the P2X7R was reported to increase the risk of recurrence of TB ( Fernando et al, 2007 ). In infectious inflammatory diseases the roles of P2X7R and ectonucleotidases have been reviewed ( Morandini et al, 2014 ).…”

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

“…The use of P2X7R agonists in conjunction with low molecular weight anti-bacterial medicines has been proposed for the treatment of multi-drug-resistant tuberculosis [ 25 ]. P2X7R antagonists are potential tools for the treatment of Clostridium perfringens type C [ 26 ] and Porphyromonas gingivalis [ 27 ] infections.…”