Abstract
The cytochrome bcc:aa3 oxidase is the target of telacebec, a clinically advanced drug developed for Mycobacterium tuberculosis. However, telacebec is inactive against Mycobacterium abscessus, an opportunistic pathogen increasingly linked to chronic pulmonary infections and notoriously known for intrinsic resistance to numerous antibiotics. Here, we report the 2.6 Å cryo-electron microscopy structure of the M. abscessus bcc:aa3 cytochrome oxidase supercomplex, revealing key pathways and the evolution of the mycobacterial QcrB menaquinol-binding cavity. Structure-guided mutagenesis identified polymorphisms that modulate telacebec binding and potency in both M. abscessus and Mycobacterium smegmatis. Leveraging these insights, we designed ND-011458, a QcrB inhibitor with potent activity against M. abscessus and being bactericidal in combination with Clofazimine. The 2.26 Å inhibitor-bound structure elucidates its binding mode and provides a framework for the design of next-generation inhibitors for M. abscessus pulmonary diseases.
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Data availability
All relevant data are contained within the article. Structural data that supports the findings of this study are openly available from the Protein Data Bank (https://www.rcsb.org; PDB ID 9WCX, 9WCY) and the EM Data Bank (https://www.ebi.ac.uk/emdb/; EMDB ID EMD-65878, EMD-65879). Source data are provided with this paper.
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Acknowledgements
The authors acknowledge the Cryo-Electron Microscopy Facility at the Center for Bioimaging Science, Department of Biological Science, National University of Singapore for technical assistance in data collection of the apo enzyme complex. We also acknowledge the NTU Institute of Structural Biology, Nanyang Technological University, Singapore for the usage of the Cryo-Electron Microscopy Facility for the compound-bound enzyme complex. This work was supported by the National Research Foundation (NRF) Singapore, NRF Competitive Research Programme (CRP), Grant Award Number NRF-CRP27-2021-0002. E.T.X.Y. was funded by an NTU Research Scholarship. G.M. was supported by grant R37AI054193 by the National Institute of Health (NIH), United States. Funding for the Montana State Mass Spectrometry Facility (RRID: SCR_012482) used in this publication was made possible in part by the MJ Murdock Charitable Trust, the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers P20GM103474 and S10OD28650, and the MSU Office of Research and Economic Development. NMR spectra were recorded at Montana State University on a 400 MHz NMR spectrometer housed in MSU’s NMR Center (RRID:SCR_026334). Financial support for the NMR instruments and operations have been provided in part by the NIH SIG program (1S10RR13878 and 1S10RR026659), the National Science Foundation (NSF-MRI:DBI-1532078; NSF-MRI:CHE-2018388), the Murdock Charitable Trust Foundation (2015066:MNL), and MSU’s Office of Research & Economic Development, and Graduate Education at MSU.
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V.M., E.T.X.Y., G.M. and G.G. designed the experiments; V.M., E.T.X.Y., G.M., S.B. and G.G. formal analysis; V.M., E.T.X.Y., G.M., S.B., W.-G.S. investigation; V.M. and G.G. writing-original draft; all authors; Writing - Review and Editing; G.M., K.P. and G.G. funding acquisition.
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G.G, V.M., G.M, and P.K. are inventors on the patent 63/773,541, which is related to the inhibitor described in this article. The remaining authors declare no competing interests.
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Mathiyazakan, V., Tan, E.X.Y., Moraski, G. et al. The Mycobacterium abscessus cytochrome bcc:aa3 oxidase structure paves the way for an agent targeting subunit QcrB. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70805-5
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DOI: https://doi.org/10.1038/s41467-026-70805-5
