The Mycobacterium abscessus cytochrome bcc:aa3 oxidase structure paves the way for an agent targeting subunit QcrB

  • Nat Commun. 2026 Apr 3;17(1):4821. doi: 10.1038/s41467-026-70805-5.
Vikneswaran Mathiyazakan  1 ,  Emilia Xin Yi Tan  1 ,  Garrett Moraski  2 ,  Sandip Basak  1  3 ,  Wuan-Geok Saw  3 ,  Kevin Pethe  4  5  6  7 ,  Gerhard Grüber  8
Affiliations
  • 1. School of Biological Sciences, Nanyang Technological University, Singapore, Republic of Singapore.
  • 2. Montana State University, 103 Chemistry and Biochemistry Building, Bozeman, MT, USA.
  • 3. NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
  • 4. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Republic of Singapore.
  • 5. National Centre for Infectious Diseases (NCID), Singapore, Singapore.
  • 6. Singapore Centre on Environmental Life Sciences Engineering (SCELSE), Singapore, Singapore.
  • 7. Ineos Oxford Institute for Antimicrobial Research (IOI), Department of Biology, University of Oxford, Oxford, UK.
  • 8. School of Biological Sciences, Nanyang Technological University, Singapore, Republic of Singapore. [email protected].
PMID: 41932870 DOI: 10.1038/s41467-026-70805-5
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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