A human xenobiotic nuclear receptor contributes to nonresponsiveness ofto the antituberculosis drug rifampicin.

Bhagyaraj, Ella and Tiwari, Drishti and Ahuja, Nancy and Nanduri, Ravikanth and Saini, Ankita and Kalra, Rashi and Kumar, Sumit and Janmeja, Ashok Kumar and Gupta, Pawan (2018) A human xenobiotic nuclear receptor contributes to nonresponsiveness ofto the antituberculosis drug rifampicin. The Journal of biological chemistry, 293 (10). pp. 3747-3757. ISSN 1083-351X

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Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug-efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug-efflux transporters in macrophages. This was evident from expression analysis of drug-efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug-efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug-efflux systems of the host.

Item Type: Article
Additional Information: Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
Uncontrolled Keywords: Drug nonresponsiveness; Mycobacterium tuberculosis; PXR; drug resistance; drug transport; nuclear receptor; tuberculosis
Subjects: Q Science > QR Microbiology
Depositing User: Dr. K.P.S.Sengar
Date Deposited: 27 Mar 2018 04:40
Last Modified: 27 Mar 2018 04:40
URI: http://crdd.osdd.net/open/id/eprint/2009

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