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. Nguyen, Anh T. V. Nguyen, Ha Phan, Carol Wilusz, Brendan K. Podell, Dira Sanoussi N’, Bouke C. 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. Vásquez and Martin I. Voskuil ()
Additional contact information
Nicholas D. Walter: Rocky Mountain Regional VA Medical Center
Sarah E. M. Born: University of Colorado Anschutz Medical Campus
Gregory T. Robertson: Consortium for Applied Microbial Metrics
Matthew Reichlen: University of Colorado Anschutz Medical Campus
Christian Dide-Agossou: Colorado School of Public Health
Victoria A. Ektnitphong: Colorado State University
Karen Rossmassler: Rocky Mountain Regional VA Medical Center
Michelle E. Ramey: Colorado State University
Allison A. Bauman: Colorado State University
Victor Ozols: Rocky Mountain Regional VA Medical Center
Shelby C. Bearrows: Rocky Mountain Regional VA Medical Center
Gary Schoolnik: Stanford University
Gregory Dolganov: Stanford University
Benjamin Garcia: National Jewish Health
Emmanuel Musisi: Infectious Disease Research Collaboration
William Worodria: Infectious Disease Research Collaboration
Laurence Huang: University of California San Francisco
J. Lucian Davis: Yale School of Public Health
Nhung V. Nguyen: Vietnam National TB Programme/UCSF Research Collaboration Unit
Hung V. Nguyen: Vietnam National TB Programme/UCSF Research Collaboration Unit
Anh T. V. Nguyen: Vietnam National TB Programme/UCSF Research Collaboration Unit
Ha Phan: Vietnam National TB Programme/UCSF Research Collaboration Unit
Carol Wilusz: Colorado State University
Brendan K. Podell: Colorado State University
Dira Sanoussi N’: Laboratoire de Référence des Mycobactéries
Bouke C. Jong: Institute of Tropical Medicine
Corinne S. Merle: London School of Hygiene and Tropical Medicine
Dissou Affolabi: Laboratoire de Référence des Mycobactéries
Helen McIlleron: University of Cape Town
Maria Garcia-Cremades: University of California San Francisco
Ekaterina Maidji: University of California San Francisco
Franceen Eshun-Wilson: University of California San Francisco
Brandon Aguilar-Rodriguez: University of California San Francisco
Dhuvarakesh Karthikeyan: University of California San Francisco
Khisimuzi Mdluli: Bill & Melinda Gates Medical Research Institute
Cathy Bansbach: Bill and Melinda Gates Foundation
Anne J. Lenaerts: Colorado State University
Radojka M. Savic: Consortium for Applied Microbial Metrics
Payam Nahid: Consortium for Applied Microbial Metrics
Joshua J. Vásquez: Consortium for Applied Microbial Metrics
Martin I. Voskuil: Consortium for Applied Microbial Metrics

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22833-6

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