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

• Type of Material: Article
• Authors: Ruth J. Napier, Emory University; Wasiulla Rafi, University of Medicine and Dentistry of New Jersey; Mani Cheruvu, Centers for Disease Control and Prevention; Kimberly Robin Powell, Emory University; M. Analise Zaunbrecher, Emory University; William Bornmann, MD Anderson Cancer Center; Padmini Salgame, University of Medicine and Dentistry of New Jersey; Thomas M. Shinnick, Emory University; Daniel Kalman, Emory University
• Language: English
• Date: 2011-11-17
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016%2Fj.chom.2011.09.010
• Title of Journal or Parent Work: Cell Host and Microbe
• ISSN: 1931-3128
• Volume: 10
• Issue: 5
• Start Page: 475
• End Page: 485
• Grant/Funding Information: This work was supported by NCICA016672 (to W.B), and by R01A107246201, R01AI056067–01 and a grant from the Bio-Merieux Foundation (all to D.K.).
• Keywords: Drug resistance; tyrosine kinase; XDR TB; Gleevec®
• Research Categories: Biology, Genetics; Health Sciences, Pathology; Biology, Microbiology

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.