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Phenotyping resistance to bedaquiline and emerging medicines assessment by a fast RNA-based drug susceptibility test: TRACeR-TB

A Sury(1,2,3) M Maex(1,2) A Baulard(4) F Sayes(5) W Frigui(5) R Brosch(5) L Rigouts(6) P Cos(3) V Mathys(1,2) P J Ceyssens(1,2) A Van den Bossche(1,2)

1:Scientific Service Bacterial Diseases - Infectious Diseases in Humans, Sciensano, Brussels, Belgium; 2:National Reference Center of Mycobacteria and tuberculosis - Infectious Diseases in Humans, Sciensano, Brussels, Belgium; 3:Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Science, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium; 4:Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France; 5:Institut Pasteur, Université Paris Cité, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 6047, Paris, France; 6:Mycobacteriology Unit, Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Since bedaquiline (BDQ) has become a core drug in drug-resistant tuberculosis therapy, rapid and accurate  drug-susceptibility testing (DST) is of major importance. Currently, molecular mechanisms leading to BDQ resistance have not been fully elucidated, and only provisional MIC breakpoints and critical concentrations exist for pDST. To dramatically speed up pDST for M. tuberculosis, we previously developed TRACeR-TB, an assay based on the quantification of antibiotic-specific RNA biomarkers, based on the principle that antibiotic exposure triggers transcriptional stress responses in susceptible but not in resistant microbes, enabling the distinction between resistant and susceptible strains in only a few days. By focusing on a general stress response rather than the resistance mechanism itself, TRACeR-TB is an efficient tool to complete the knowledge on genotypic-phenotypic associations. At ESM, we will present TRACeR-TB results that outcompetes MGIT-DST for BDQ. In combination with WGS, this fast assay can be of great value to enrich or curate drug-resistance/WGS databases (e.g. WHO Catalogue of mutations). In this study, we compared TRACeR-TB outcomes from strains carrying mutations known to be associated with resistance or of uncertain significance in three key genes: pepQ, Rv0678 and atpE.  All mutants were identified as low or moderate/high-level BDQ-resistant, while MGIT-DST found some to be BDQ susceptible. Our tool  can therefore give new insights into resistance conferring mutations. In addition, we will present how TRACeR-TB can be applied to investigate novel medicines that boost antibiotic efficiency or to assess in vivo drug responses in a macrophage model.

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