title: Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis.
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.
authors.affiliation: Graduate Program of Microbiology and Molecular Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Napier
authors.forename: Wasiulla
authors.initials: W
authors.lastname: Rafi
authors.forename: Mani
authors.initials: M
authors.lastname: Cheruvu
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Powell
authors.forename: M Analise
authors.initials: MA
authors.lastname: Zaunbrecher
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Padmini
authors.initials: P
authors.lastname: Salgame
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Shinnick
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalman
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides; D002460:Cell Line; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*; D014774:Virulence
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases
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