Background and methods
Although curable, tuberculosis (TB) remains a top ten cause of death globally, partly due to its prolonged treatment time, currently comprised of several drugs for 6-12 months (1). As such, the discovery of novel strategies to decrease treatment time is paramount to global TB management. LirAB is an acid-sensing two-component regulatory system of Mycobacterium tuberculosis, the etiological agent of TB, comprised of the sensor histidine kinase LirB and response regulator LirA. Here we investigated the role of LirAB in virulence and the potential of LirAB targeting to improve treatment efficiency in a murine model of TB. A doxycycline-inducible CRISPR-dCas9 based gene silencing system was employed to knockdown lirA expression in virulent M. tuberculosis, H37Rv (2). A murine model of TB was employed to investigate the impact of lirA knockdown during infection, and the consequence of lirA knockdown to TB treatment with two frontline drugs, rifampicin and isoniazid.
Results and conclusions
Transcriptional silencing of lirA significantly attenuated the persistence of H37Rv in a murine model of TB. Alongside treatment with rifampicin and isoniazid, the knockdown of lirA resulted in a statistically significant 1-log reduction in mycobacterial burden in the lungs and spleens of infected mice, as compared to mice in which lirA remained active. We have identified and validated an attractive inhibitory target to improve the treatment of TB and potentially shorten therapy duration. Our efforts are now invested toward the discovery of novel small molecule inhibitors of the LirAB system.
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