TY - JOUR
T1 - Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens
AU - Walter, Nicholas D.
AU - Born, Sarah E. M.
AU - Robertson, Gregory T.
AU - Reichlen, Matthew
AU - Dide-Agossou, Christian
AU - Ektnitphong, Victoria A.
AU - Rossmassler, Karen
AU - Ramey, Michelle E.
AU - Bauman, Allison A.
AU - Ozols, Victor
AU - Bearrows, Shelby C.
AU - Schoolnik, Gary
AU - Dolganov, Gregory
AU - Garcia, Benjamin
AU - Musisi, Emmanuel
AU - Worodria, William
AU - Huang, Laurence
AU - Davis, J. Lucian
AU - Nguyen, Nhung V.
AU - Nguyen, Hung V.
AU - Nguyen, Anh T. V.
AU - Phan, Ha
AU - Wilusz, Carol
AU - Podell, Brendan K.
AU - Sanoussi, N' Dira
AU - de Jong, Bouke C.
AU - Merle, Corinne S.
AU - Affolabi, Dissou
AU - McIlleron, Helen
AU - Garcia-Cremades, Maria
AU - Maidji, Ekaterina
AU - Eshun-Wilson, Franceen
AU - Aguilar-Rodriguez, Brandon
AU - Karthikeyan, Dhuvarakesh
AU - Mdluli, Khisimuzi
AU - Bansbach, Cathy
AU - Lenaerts, Anne J.
AU - Savic, Radojka M.
AU - Nahid, Payam
AU - Vasquez, Joshua J.
AU - Voskuil, Martin I.
N1 - FTX; DOAJ; (CC BY 4.0)
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Animals
KW - Antitubercular Agents/administration & dosage
KW - Disease Models, Animal
KW - Female
KW - Humans
KW - Mice, Inbred BALB C
KW - Mycobacterium tuberculosis/drug effects
KW - RNA Precursors/genetics
KW - RNA, Bacterial/genetics
KW - RNA, Ribosomal/genetics
KW - Treatment Outcome
KW - Tuberculosis/diagnosis
U2 - 10.1038/s41467-021-22833-6
DO - 10.1038/s41467-021-22833-6
M3 - A1: Web of Science-article
C2 - 34006838
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2899
ER -