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Exploring the impact of mutations in Rv0678 gene on bedaquiline resistance in Mycobacterium tuberculosis: insights from computational biostructural proteomics

J Snobre(1,2,3) L Rigouts(1) B C de Jong(1) O Tzfadia(1)

1:Mycobacteriology Unit, Biomedical Sciences, Institute of Tropical Medicine (ITM), Antwerp, Belgium; 2:Doctoral School of Life Sciences & Medicine, Vrije Universiteit Brussel , Brussels, Belgium; 3:Internal Medicine Department, UZ Brussel, Brussels, Belgium

Drug-resistant tuberculosis is a significant global health concern. Bedaquiline (BDQ) is a relatively new drug that targets Mycobacterium tuberculosis by disrupting its respiratory chain. Resistance to BDQ has been linked to mutations in the Rv0678 gene, which regulates the efflux pump MmpS5-MmpL5. Previous attempts to identify Rv0678 genomic hotspots with phenotypic resistance to BDQ have not been successful, possibly due to the limitation of only considering linear sequence (1D) rather than potential mutations clusters on the protein tertiary structure (3D) as well as not taking into account alternative reading frames.

In this study, we used computational tools such as PDBpisa, Alpha Fold2 and SurfMap on a dataset of 224 isolates including in vitro selected and clinical isolates presenting a Rv0678 mutation to study the impact of SNPs and frameshift mutations on the protein structure and final impact on BDQ MIC.

Results suggest the existence of mutations clustering in the Rv0678 tertiary structure, corresponding to the DNA-binding domain. Analysis of frameshift mutations in clinical isolates shows that they are primarily located in the initial 200 nucleotides of the protein. We also found that despite significant changes to the primary amino-acid sequence, some frameshifted proteins encoded by alternative reading frames have similar structures to the wild-type protein. Finally, different mutations clustering patterns in vitro selected and clinical isolates suggest that in vivo factors may have an impact on mutants’ selection. Overall, our findings help bridge the genotypic-phenotypic gap in BDQ resistance and advance toward the development of a diagnostic molecular test.

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