Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach (original) (raw)

Confirmatory Results

, Joshua Carter, View ORCID ProfileAndrea Spitaleri, View ORCID ProfileZamin Iqbal, Martin Hunt, View ORCID ProfileKerri Malone, Christian Utpatel, View ORCID ProfileDaniela Maria Cirillo, Camilla Rodrigues, Kayzad S. Nilgiriwala, the CRyPTIC Consortium, View ORCID ProfilePhilip W. Fowler, View ORCID ProfileMatthias Merker, View ORCID ProfileStefan Niemann

doi: https://doi.org/10.1101/2021.03.19.436148

Abstract

Bedaquiline (BDQ) and clofazimine (CFZ) are core drugs for treatment of multidrug resistant tuberculosis (MDR-TB), however, our understanding of the resistance mechanisms for these drugs is sparse which is hampering rapid molecular diagnostics. To address this, we employed a unique approach using experimental evolution, protein modelling, genome sequencing, and minimum inhibitory concentration data combined with genomes from a global strain collection of over 14,151 Mycobacterium tuberculosis complex isolates and an extensive literature review. Overall, 230 genomic variants causing elevated BDQ and/or CFZ MICs could be discerned, with 201 (87.4%) variants affecting the transcriptional repressor (Rv0678) of an efflux system (mmpS5-mmpL5). Structural modelling of Rv0678 suggests four major mechanisms that confer resistance: impairment of DNA binding, reduction in protein stability, disruption of protein dimerization, and alteration in affinity for its fatty acid ligand. These modelling and experimental techniques will improve personalized medicine in an impending drug resistant era.

Competing Interest Statement

The authors have declared no competing interest.

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