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

Nature communications, Volume: 12, Issue: 1
May 18, 2021
Nicholas D Walter ND, Sarah E M Born SEM, Gregory T Robertson GT, Matthew Reichlen M, Christian Dide-Agossou C, Victoria A Ektnitphong VA, Karen Rossmassler K, Michelle E Ramey ME, Allison A Bauman AA, Victor Ozols V, Shelby C Bearrows SC, Gary Schoolnik G, Gregory Dolganov G, Benjamin Garcia B, Emmanuel Musisi E, William Worodria W, Laurence Huang L, J Lucian Davis JL, Nhung V Nguyen NV, Hung V Nguyen HV, Anh T V Nguyen ATV, Ha Phan H, Carol Wilusz C, Brendan K Podell BK, N' Dira Sanoussi ND, Bouke C de Jong BC, Corinne S Merle CS, Dissou Affolabi D, Helen McIlleron H, Maria Garcia-Cremades M, Ekaterina Maidji E, Franceen Eshun-Wilson F, Brandon Aguilar-Rodriguez B, Dhuvarakesh Karthikeyan D, Khisimuzi Mdluli K, Cathy Bansbach C, Anne J Lenaerts AJ, Radojka M Savic RM, Payam Nahid P, Joshua J Vásquez JJ, Martin I Voskuil MI

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.

Courtesy of the U.S. National Library of Medicine