Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens

Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens. Walter, N. D, Born, S. E M, Robertson, G. T, Reichlen, M., Dide-Agossou, C., Ektnitphong, V. A, Rossmassler, K., Ramey, M. E, Bauman, A. A, Ozols, V., Bearrows, S. C, Schoolnik, G., Dolganov, G., Garcia, B., Musisi, E., Worodria, W., Huang, L., Davis, J. L., Nguyen, N. V, Nguyen, H. V, Nguyen, A. T V, Phan, H., Wilusz, C., Podell, B. K, Sanoussi, N. D., de Jong, B. C, Merle, C. S, Affolabi, D., McIlleron, H., Garcia-Cremades, M., Maidji, E., Eshun-Wilson, F., Aguilar-Rodriguez, B., Karthikeyan, D., Mdluli, K., Bansbach, C., Lenaerts, A. J, Savic, R. M, Nahid, P., Vásquez, J. J, & Voskuil, M. I Nature Communications, 12(1):2899, Nature Publishing Group, dec, 2021.

Paper doi abstract bibtex

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.

@article{Walter2021,
abstract = {There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.},
author = {Walter, Nicholas D and Born, Sarah E M and Robertson, Gregory T and Reichlen, Matthew and Dide-Agossou, Christian and Ektnitphong, Victoria A and Rossmassler, Karen and Ramey, Michelle E and Bauman, Allison A and Ozols, Victor and Bearrows, Shelby C and Schoolnik, Gary and Dolganov, Gregory and Garcia, Benjamin and Musisi, Emmanuel and Worodria, William and Huang, Laurence and Davis, J. Lucian and Nguyen, Nhung V and Nguyen, Hung V and Nguyen, Anh T V and Phan, Ha and Wilusz, Carol and Podell, Brendan K and Sanoussi, N' Dira and de Jong, Bouke C and Merle, Corinne S and Affolabi, Dissou and McIlleron, Helen and Garcia-Cremades, Maria and Maidji, Ekaterina and Eshun-Wilson, Franceen and Aguilar-Rodriguez, Brandon and Karthikeyan, Dhuvarakesh and Mdluli, Khisimuzi and Bansbach, Cathy and Lenaerts, Anne J and Savic, Radojka M and Nahid, Payam and V{\'{a}}squez, Joshua J and Voskuil, Martin I},
doi = {10.1038/s41467-021-22833-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Walter et al. - 2021 - iMycobacterium tuberculosisi precursor rRNA as a measure of treatment-shortening activity of drugs and regimens.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {Antibiotics,Bacterial transcription,Infectious,OA,Tuberculosis,disease diagnostics,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {dec},
number = {1},
pages = {2899},
pmid = {34006838},
publisher = {Nature Publishing Group},
title = {{\textit{Mycobacterium tuberculosis} precursor rRNA as a measure of treatment-shortening activity of drugs and regimens}},
url = {http://www.nature.com/articles/s41467-021-22833-6},
volume = {12},
year = {2021}
}

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