Tuberculosis is the single leading cause of death from a curable infectious disease and is becoming progressively incurable due to the spread of drug resistance. This project explores a work-around for resistance of M. tuberculosis (Mtb) to anti-infectives: inhibiting protein kinase R (PKR) in the host. Mtb depends on PKR to cause full-blown disease. We recently discovered that PKR-deficient mice infected with Mtb have markedly reduced bacterial burden and histopathology. The mechanism involves PKR's ability to restrain the extent to which macrophages undergo classical activation by interferon-gamma (IFN?) and microbial products. PKR restrains macrophage activation by linking IFN? signaling to the production of small amounts of interleukin-10 (IL10), a macrophage de-activating factor. We identified a novel inhibitor of PKR that phenocopied PKR deficiency in producing "super-activation" of macrophages in the presence of IFN? or the combination of IFN? and Mtb, as reflected by reduced production of IL10 and elevated production of nitric oxide and tumor necrosis factor (TNF). Small-molecule super-activators of macrophages (SAMs) could offer a novel, adjunctive approach to the treatment of chronic infections without the potential for selection of drug-resistance in the pathogen. We will explore Celgene's extensive library of kinase inhibitors to identify potent, relatively selective inhibitors of PKR and characterize them as SAMs in vitro and in Mtb-infected mice.
Tuberculosis is the single leading cause of death from a curable infectious disease and is becoming progressively harder to treat because of drug resistance. This project aims to develop a new kind of drug for TB: a chemical compound that inhibits an enzyme in the host, not in the pathogen. The TB bacillus counts on a host enzyme called PKR to hold back the full force of the host immune system, specifically, to limit the activation of macrophages, a cell in which the pathogen persists during much of the course of infection. Inhibitors of PKR allow macrophages to mount a stronger attack on the tubercle bacilli than we had thought they were capable of doing. Since such inhibitors do not act by entering the bacterium, it will be difficult for the bacterium to develop resistance to them. Super-activators of macrophages might be used in conjunction with conventional anti-bacterial agents to treat chronic bacterial infections.