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Phenotyping resistance to new and emerging medicines by a fast RNA‑based drug susceptibility test

A Sury(1,3) M Maex(1) A Huyghebaert(1) A Baulard(2) R Brosch(4) M Monot(4) I Mokrousov(5) D Cappoen(3) P Cos(3) V Mathys(1) P Ceyssens(1) A Van den Bossche(1)

1:Sciensano; 2:Institut Pasteur de Lille; 3:University of Antwerp; 4:Institut Pasteur de Paris; 5:Petersburg Pasteur Institute

Current standard phenotypic drug susceptibility testing (pDST) of Mycobacterium tuberculosis takes 5-8 weeks. While DNA-based methods have strongly increased the TB diagnostic capacity worldwide, they are de facto based on pDST results, which will continue to be required in the future considering that new therapeutic approaches are being developed and new resistance mutations emerge regularly. To dramatically speed up the pDST of M. tuberculosis, we previously developed and validated a pDST based on the quantification of antibiotic-specific RNA biomarkers for a set of first and second-line drugs. The basic principle is that an antibiotic exposure triggers transcriptional stress responses in susceptible but not in resistant microbes, enabling the distinction between resistant and susceptible strains in only few days. By focusing on a general stress response rather than the resistance mechanism itself, this tool could help in closing the diagnostic gap. At ESM, we will present results of RNAseq based biomarker discovery, as well as assay design and optimisation for new and repurposed antibiotics, like bedaquilin, linezolid, delamanid, pretomanid and macozinone, and show that a proper distinction can be made between sensitive and resistant strains. Finally, we demonstrate that our tool can be used to investigate molecules that boost antibiotic efficiency, such as the recently published compound that restores ethionamide efficacy.

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