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
Full text not available from this repository. (Request a copy)Abstract
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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