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

Nicholas D. Walter, Sarah E. M. Born, Gregory T. Robertson, Matthew Reichlen, Christian Dide-Agossou, Victoria A. Ektnitphong, Karen Rossmassler, Michelle E. Ramey, Allison A. Bauman, Victor Ozols, Shelby C. Bearrows, Gary Schoolnik, Gregory Dolganov, Benjamin Garcia, Emmanuel Musisi, William Worodria, Laurence Huang, J. Lucian Davis, Nhung V. Nguyen, Hung V. NguyenAnh T. V. Nguyen, Ha Phan, Carol Wilusz, Brendan K. Podell, N' Dira Sanoussi, Bouke C. de Jong, Corinne S. 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. Savic, Payam Nahid, Joshua J. Vasquez, Martin I. Voskuil

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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.

Original languageEnglish
Article number2899
JournalNature Communications
Volume12
Issue number1
Number of pages11
ISSN2041-1723
DOIs
Publication statusPublished - 2021

Keywords

  • Animals
  • Antitubercular Agents/administration & dosage
  • Disease Models, Animal
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis/drug effects
  • RNA Precursors/genetics
  • RNA, Bacterial/genetics
  • RNA, Ribosomal/genetics
  • Treatment Outcome
  • Tuberculosis/diagnosis

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