Transcriptome signature of cell viability predicts drug response and drug interaction for Tuberculosis

Abstract

The treatment of tuberculosis (TB), which kills 1.8 million each year, remains difficult, especially with the emergence of multidrug resistant strains of Mycobacterium tuberculosis (Mtb). While there is an urgent need for new drug regimens to treat TB, the process of drug evaluation is slow and inefficient owing to the slow growth rate of the pathogen, the complexity of performing bacteriologic assays in a high-containment facility, and the context-dependent variability in drug sensitivity of the pathogen. Here, we report the development of DRonA and MLSynergy, algorithms to perform rapid drug response assays and predict response of Mtb to novel drug combinations. Using a novel transcriptome signature for cell viability, DRonA accurately detects bacterial killing by diverse mechanisms in broth culture, macrophage infection and patient sputum, providing an efficient, and more sensitive alternative to time- and resource-intensive bacteriologic assays. Further, MLSynergy builds on DRonA to predict novel synergistic and antagonistic multi-drug combinations using transcriptomes of Mtb treated with single drugs. Together DRonA and MLSynergy represent a generalizable framework for rapid monitoring of drug effects in host-relevant contexts and accelerate the discovery of efficacious high-order drug combinations.

MadR mediates acyl CoA-dependent regulation of mycolic acid desaturation in mycobacteria

“…Interestingly, Δ madR also showed increased sensitivity to INH (4 µg/mL) compared to the WT and complemented strains (8 µg/mL). In WT M. tuberculosis , desA1 / desA2 are significantly down-regulated in response to 0.18 µg/mL INH for 4, 24, and 72 h (at 24 h, log 2 fold change = −2.50 and −2.712 for desA1 and desA2 , respectively; P < 0.01), and, therefore, the inability of MadR to repress expression may account for this increased susceptibility in the deletion strain ( 30 , 31 ). There was no change in the MIC for ETM between the strains.…”