TY  - JOUR
N1  - Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
ID  - open2009
UR  - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=29358328
IS  - 10
A1  - Bhagyaraj, Ella
A1  - Tiwari, Drishti
A1  - Ahuja, Nancy
A1  - Nanduri, Ravikanth
A1  - Saini, Ankita
A1  - Kalra, Rashi
A1  - Kumar, Sumit
A1  - Janmeja, Ashok Kumar
A1  - Gupta, Pawan
Y1  - 2018/03/09/
N2  -   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.
PB  - American Society for Biochemistry and Molecular Biology
JF  - The Journal of biological chemistry
VL  - 293
KW  - Drug nonresponsiveness; Mycobacterium tuberculosis; PXR; drug resistance; drug transport; nuclear receptor; tuberculosis
SN  - 1083-351X
TI  - A human xenobiotic nuclear receptor contributes to nonresponsiveness ofto the antituberculosis drug rifampicin.
SP  - 3747
EP  - 3757
ER  -