The Mycobacterium abscessus cytochrome bcc:aa3 oxidase structure paves the way for an agent targeting subunit QcrB
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
- Gerhard Grüber (ORCID: https://orcid.org/0000-0002-5730-8319)
- Wuan Geok Saw (ORCID: https://orcid.org/0000-0002-2510-387X)
- Vikneswaran Mathiyazakan (ORCID: https://orcid.org/0000-0002-2934-278X)
- Kévin Pethe (ORCID: https://orcid.org/0000-0003-0916-8873)
- Garrett C. Moraski (ORCID: https://orcid.org/0000-0002-6992-5584)
- Emilia Xin Yi Tan
- Sandip Basak
Institutions
- Nanyang Technological University (SG)
- Montana State University (US)
- CRUK/MRC Oxford Institute for Radiation Oncology (GB)
- Singapore Centre for Environmental Life Sciences Engineering (SG)
- National Centre for Infectious Diseases (SG)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-03
- DOI
- https://doi.org/10.1038/s41467-026-70805-5
- Primary Topic
- Metal-Catalyzed Oxygenation Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National University of Singapore
- National Research Foundation Singapore