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

作者：Nicholas D. Walter, Sarah E. M. Born, Gregory T. Robertson, Matthew J. Reichlen, Christian Dide-Agossou, Victoria Ektnitphong, Karen Rossmassler, Michelle E. Ramey, Allison Bauman, Victor Ozols, Shelby C. Bearrows, Gary K. Schoolnik, Gregory Dolganov, Benjamin J. Garcia, Emmanuel Musisi, William Worodria, Laurence Huang, J. Lucian Davis, Nguyen Viet Nhung, Hung Van Nguyen, Nguyễn Thị Vân Anh, Ha Phan, Carol J. Wilusz, Brendan K. Podell, N Sanoussi, Bouke C. de Jong, Corinne Merle, Dissou Affolabi, Helen McIlleron, Maria Garcia‐Cremades, Ekaterina Maidji, Franceen Eshun‐Wilson, Brandon Aguilar-Rodriguez, Dhuvarakesh Karthikeyan, Khisimuzi Mdluli, Cathy Bansbach, Anne J. Lenaerts, Radojka M. Savić, Payam Nahid, Joshua Vasquez, Martin I. Voskuil · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-22833-6 · 被引用次数：101 · 研究领域：Tuberculosis Research and Epidemiology、Mycobacterium research and diagnosis、RNA and protein synthesis mechanisms

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.