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Using long term evolution models to define drug resistance mechanisms to DDU209, a novel tuberculosis drug candidate

L Sonnenkalb(1) C Gaudin(2) L Cleghorn(3) S Green(3) S Niemann(1,4)

1:Research Center Borstel Leibniz Lung Centre; 2:Institut Pasteur Lille; 3:Dundee University; 4:German Centre for Infection Research

Nearly all drugs developed for tuberculosis (TB) treatment lack testing and surveillance strategies when released for commercial use. To better protect new anti-TB drugs and reduce rampant resistance development, molecular and phenotypic assays should be developed alongside the drug and utilized upon commercial use.

We established an in vitro evolutionary model which employs low-concentration drug exposure to select mutants with an array of resistant phenotypes which predicated well resistance mechanisms for bedaquiline similar to clinical Mycobacterium tuberculosis complex (Mtbc) strains.  In the framework of ERA4TB, a large consortium dedicated to the development of new treatment regimens for TB, we applied our method to the novel compound DDU-209, a promising drug candidate developed at Dundee University, which inhibits lysyl-tRNA synthase. We found five genes potentially related to DDU-209 resistance, with the most important resistance determining region (RDR) throughout Rv3598c-Rv3599c. This region is essential to bacterial survival, where single nucleotide polymorphisms, codon deletion, and even gene duplication were identified as modes of resistance. With the mutation catalogues generated, we found phylogenetic SNPs in clinical Mtbc strains in the defined RDR. Finally, with this collection of mutant clones we found no cross-resistance with other anti-TB drugs. With the future publication of this and other work produced by ERA4TB we will have a better standing on surveillance and treatment strategies for DDU-209 and other novel and repurposed drugs.

This work reflects only the author's views, and the JU is not responsible for any use that may be made of the information it contains.

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