Investigation of delamanid, bedaquiline, and linezolid resistance rates and related gene mutations in multidrug-resistant Mycobacterium tuberculosis in regional tuberculosis reference laboratories of Iran.

INTRODUCTION: So far, there are scarce data on resistance to delamanid (DLM), bedaquiline (BDQ), and linezolid (LZD) antibiotics and related gene mutations in multidrug-resistantMDR) from Iran. Hence, this study aimed to investigate the DLM, BDQ, and LZD resistance rates and related gene mutations in MDRin regional tuberculosis reference laboratories of Iran.

METHODS: In this cross-sectional study, MDRisolates (resistant to antibiotics rifampicin and isoniazid) were collected from sputum samples of tuberculosis patients referred to several regional tuberculosis reference laboratories in Iran. The resistance against DLM, BDQ, and LZD antibiotics was evaluated using the proportion method on the Middlebrook 7H11 agar culture medium. The minimum inhibitory concentration (MIC) of three antibiotics was evaluated using the broth microdilution method. Mutations in genes that contributed to resistance to antibiotics DLM (,,,), BDQ (,,), and LZD (and) were investigated by polymerase chain reaction (PCR) and sequencing.

RESULTS: This study examined 29 clinical MDRisolates. These isolates were collected from 68.9% (20/29) males and 31.1% (9/29) females with a mean age of 40 years (ranged 30–70 years). The resistance rate to DLM, BDQ, and LZD was 27.6% ( = 8/29), 0.0% ( = 0/29), and 6.8% ( = 2/29), respectively. The range of MIC for DLM was 0.12–0.48 µg/ml. Meanwhile, the 2 LZD-resistant isolates showed MIC of 2.0 µg/ml. All MDRisolates with phenotypic resistance to DLM (8 isolates) contained mutations in one of the,, andgenes. A mutation was identified in the 1090 bp fragment of the fgd1 gene at position 839 in five isolates. Additionally, the 2386 bp fragment of thegene revealed mutations at positions 266 and 952 in three isolates. Also, two DLM-resistant isolates exhibited two mutations at position 145 and 960 in the 1136 bp fragment of. No genetic mutations were detected in,,, andgenes. Two LZD-resistant isolates exhibited mutations in thegene at position 460 within the 933 bp fragment, and in thegene at positions 2576 and 2814 within the 1772 bp fragment.

CONCLUSION: This study found multiple mutations in the,,,, andgenes that were responsible for the development of DLM and LZD resistance in MDRisolates in Iran. More research is needed to understand the underlying mechanisms of resistance to these antibiotics.