Determination of MİC values and resistance related mutations for novel antituberculosis drugs bedaquiline and delamanid in mycobacterium tuberculosis clinical isolates.

The purpose of this study is to detect the minimum inhibitory concentration (MIC) values of these novel drugs against to 101 resistant-M.tuberculosis clinical isolates with MGIT 960 automatized liquid culture system integrated with TB/eXİST research software as phenotypically and detection of drug resistance related mutations on bacteria genome by Sanger DNA sequencing or whole genome sequencing (WGS) as genotypically. Thirty one strains were isolated in University of Zurich, Switzerland and 70 strains were isolated in Turkey. Cross resistance between bedaquiline and clofazimin was also investigated in Swiss isolates. According to phenotypic MGIT 960 system bedaquiline, delamanid and clofazimin MIC ranges were found as <0.2 µg/ml to ≥4.0 µg/ml (mean MIC=0.92 µg/ml), ≤0.01 µg/ml to ≥3.2 µg/ml (mean MIC=0.18 µg/ml) and ≤0.5 µg/ml to ≥2.0 µg/ml (mean MIC=1.11 µg/ml), respectively. Phenotypical susceptibility test results reveal that bedaquiline MIC values of Swiss isolates were found higher than those of Turkish isolates while delamanid MIC values of isolates from Turkey were found higher than those of Swiss isolates. According to World Health Organization Critical Drug Concentration Report, mean MIC values of all of the strains were classified as sensitive to bedaquiline while they were classified as resistant to delamanid and clofazimin. Some isolates had both bedaquiline and clofazimin high MIC values but we couldn't detect any cross resistance related mutations in genome of these bacterial strains. Further studies are required to clarify new mutations related to resistance. In this study, we also tried to optimize the WGS protocol in order to detect all drug resistance profile in the genome of bacteria. The protocol could detect the resistance related variations in the genome of 25 strains. In conclusion, this study provides a preliminary AST results of M.tuberculosis strains isolated from Turkish patients for novel drugs which will be available in Turkey soon. Research software integrated MGIT 960 testing and optimized WGS protocol will be used for determination of individualised therapy of MDR-TB patients.