Imatinib-Sensitive Tyrosine Kinases Regulate Mycobacterial Pathogenesis and Represent Therapeutic Targets against Tuberculosis

Abstract

The lengthy course of treatment with currently used anti-mycobacterial drugs and the resulting emergence of drug-resistant strains have intensified the need for alternative therapies against Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. We show that Mtb and Mycobacterium marinum use Abl and related tyrosine kinases for entry and intracellular survival in macrophages. In mice, the Abl-family tyrosine kinase inhibitor, imatinib (Gleevec®), when administered prophylactically or therapeutically, reduced both the number of granulomatous lesions and bacterial load in infected organs, and was also effective against a rifampicin-resistant strain. Further, when co-administered with current first-line drugs, rifampicin or rifabutin, imatinib acted synergistically. These data implicate host tyrosine kinases in entry and intracellular survival of mycobacteria, and suggest that imatinib may have therapeutic efficacy against Mtb. Because imatinib targets host, it is less likely to engender resistance compared to conventional antibiotics, and may decrease the development of resistance against co-administered drugs.

Monocarbonyl analogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis

“…Aliquots were stored at −80 °C. For some experiments, strains with mutations that rendered M. marinum (1218R rifR ) or Mtb (H37Rv rpoB H526Y ) resistant to rifampicin were used [31]. …”

Advancing host-directed therapy for tuberculosis

“…However, two distinct mechanisms suggest a potential role for tyrosine kinase inhibitors in tuberculosis. The first is a direct, pharmacological effect on macrophage function, in which therapeutic concentrations of imatinib promote acidification and maturation of phagosomes and thereby reduce intracellular M. tuberculosis survival in vitro and in infected mice [31][32][33] . The second mechanism is indirect; at sub-therapeutic concentrations, imatinib increases neutrophil and monocyte numbers through effects on myelopoiesis, which potentially contributes to the antimycobacterial host immune response (D. Kalman, personal communication).…”

A Fluorescent Probe for Detecting Mycobacterium tuberculosis and Identifying Genes Critical for Cell Entry

“…For THP-1, phorbol 12-myristate 13-acetate (PMA) was used to stimulate the cells for 3 days. The cells were then infected with bacteria at 37°C for 3 h. After bacterial infection, extracellular bacteria were aspirated, and the infected cells were washed with 1X PBS, treated with amikacin (200 μg/ml) for additional 2 h to eliminate extracellular bacteria as described previously (Mehta et al, 1996; Napier et al, 2011). Bacterium infected cells were then fixed with 4% freshly made paraformaldehyde for 10 min at room temperature.…”