TY - JOUR
T1 - Imatinib-Sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis
AU - Napier, Ruth J.
AU - Rafi, Wasiulla
AU - Cheruvu, Mani
AU - Powell, Kimberly R.
AU - Zaunbrecher, M. Analise
AU - Bornmann, William
AU - Salgame, Padmini
AU - Shinnick, Thomas M.
AU - Kalman, Daniel
N1 - Funding Information:
We thank members of the Kalman laboratory and L. Uebelhoer, V. Faundez, and M. Sherman for helpful discussions, I. Williams and C. Parkos for pathology expertise, K. Easley for statistical advice, and J. Posey for the GFP-Mm strain. This work was supported by NCICA016672 (to W.B) and by R01A107246201, R01AI056067–01, and a grant from the Bio-Merieux Foundation (to D.K.).
PY - 2011/11/17
Y1 - 2011/11/17
N2 - The lengthy course of treatment with currently used antimycobacterial 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 coadministered 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 coadministered drugs.
AB - The lengthy course of treatment with currently used antimycobacterial 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 coadministered 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 coadministered drugs.
UR - http://www.scopus.com/inward/record.url?scp=81755161197&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=81755161197&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2011.09.010
DO - 10.1016/j.chom.2011.09.010
M3 - Article
C2 - 22100163
AN - SCOPUS:81755161197
SN - 1931-3128
VL - 10
SP - 475
EP - 485
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 5
ER -