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<p>The cytochrome <i>bcc</i>:<i>aa</i><sub>3</sub> oxidase is the target of telacebec, a clinically advanced drug developed for <i>Mycobacterium tuberculosis</i>. However, telacebec is inactive against <i>Mycobacterium abscessus</i>, 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 <i>M. abscessus bcc</i>:<i>aa</i><sub>3</sub> 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 <i>M. abscessus</i> and <i>Mycobacterium smegmatis</i>. Leveraging these insights, we designed ND-011458, a QcrB inhibitor with potent activity against <i>M. abscessus</i> 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 <i>M. abscessus</i> pulmonary diseases.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Vikneswaran Mathiyazakan,
  • Emilia Xin Yi Tan,
  • Garrett Moraski,
  • Sandip Basak,
  • Wuan-Geok Saw,
  • Kevin Pethe,
  • Gerhard Grüber

摘要

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.