The Mycobacterium abscessus cytochrome bcc: aa 3 oxidase structure paves the way for an agent targeting subunit QcrB

Journal article

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.

Authors: Mathiyazakan, V; Tan, EXY; Moraski, G; Basak, S; Saw, W

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Article number: 4821
• Publication date: 2026-04-03
• Acceptance date: 2026-03-04
• DOI: 10.1038/s41467-026-70805-5
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Protein subunit; Cytochrome c oxidase; Cytochrome; Oxidase test; Mycobacterium abscessus; Electron Transport Complex IV