Imatinib-Sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis

Ruth J. Napier, Wasiulla Rafi, Mani Cheruvu, Kimberly R. Powell, M. Analise Zaunbrecher, William Bornmann, Padmini Salgame, Thomas M. Shinnick, Daniel Kalman

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)475-485
Number of pages11
JournalCell Host and Microbe
Volume10
Issue number5
DOIs
StatePublished - Nov 17 2011
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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