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Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach

View ORCID ProfileLindsay Sonnenkalb, 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
Lindsay Sonnenkalb
1Molecular and Experimental Mycobacteriology, Research Center Borstel Leibniz Lung Center, Borstel Germany
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Joshua Carter
2Medical Scientist Training Program, Stanford University, Stanford, USA
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Andrea Spitaleri
5Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
6Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Zamin Iqbal
7European Bioinformatics Institute, Cambridge, UK
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Martin Hunt
7European Bioinformatics Institute, Cambridge, UK
8Experimental Medicine, Nuffield Department of Medicine, University of Oxford, UK
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Kerri Malone
7European Bioinformatics Institute, Cambridge, UK
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Christian Utpatel
1Molecular and Experimental Mycobacteriology, Research Center Borstel Leibniz Lung Center, Borstel Germany
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Daniela Maria Cirillo
5Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Camilla Rodrigues
9Department of Microbiology, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India
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Kayzad S. Nilgiriwala
10The Foundation for Medical Research, Mumbai, India
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11Comprehensive Resistance Prediction for Tuberculosis: an International Consortium. Author list in supplement
Philip W. Fowler
8Experimental Medicine, Nuffield Department of Medicine, University of Oxford, UK
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Matthias Merker
1Molecular and Experimental Mycobacteriology, Research Center Borstel Leibniz Lung Center, Borstel Germany
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Stefan Niemann
1Molecular and Experimental Mycobacteriology, Research Center Borstel Leibniz Lung Center, Borstel Germany
3National Reference Center, Research Center Borstel Leibniz Lung Center, Borstel Germany
4German Centre for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel, Borstel, Germany
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  • For correspondence: sniemann@fz-borstel.de
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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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 13, 2021.
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Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach
Lindsay Sonnenkalb, Joshua Carter, Andrea Spitaleri, Zamin Iqbal, Martin Hunt, Kerri Malone, Christian Utpatel, Daniela Maria Cirillo, Camilla Rodrigues, Kayzad S. Nilgiriwala, the CRyPTIC Consortium, Philip W. Fowler, Matthias Merker, Stefan Niemann
bioRxiv 2021.03.19.436148; doi: https://doi.org/10.1101/2021.03.19.436148
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Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach
Lindsay Sonnenkalb, Joshua Carter, Andrea Spitaleri, Zamin Iqbal, Martin Hunt, Kerri Malone, Christian Utpatel, Daniela Maria Cirillo, Camilla Rodrigues, Kayzad S. Nilgiriwala, the CRyPTIC Consortium, Philip W. Fowler, Matthias Merker, Stefan Niemann
bioRxiv 2021.03.19.436148; doi: https://doi.org/10.1101/2021.03.19.436148

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