Smooth-to-rough morphotype switching, a mechanism of phage resistance in Mycobacterium abscessus

• 成果类型: Article
• 署名作者: Liew, Jun Hao; Norman, Ayuni; Illouz, Morgane; Teo, Teck-Hui; Delli Ponti, Riccardo; Hamela, Claire; Mohan, Lalit; Lew, Renee; Ron, Chanvutha; Low, Kay En; Daher, Wassim; Chiam, Aryeh; Maw, Joanna; Sun, Yan; Sorayah, Ria; Oehlers, Stefan H.; Jhun, Byung Woo; Teo, Jeanette W. P.; Goulet, Adeline; Bonne, Isabelle; Wintjens, Rene; Pethe, Kevin; Huber, Roland G.; Kremer, Laurent; Bifani, Pablo
• 署名单位: Agency for Science Technology & Research (A*STAR); A*STAR Infectious Diseases Labs (A*STAR IDL); National University of Singapore; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Agency for Science Technology & Research (A*STAR); Nanyang Technological University; National University of Singapore; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Montpellier; Sungkyunkwan University (SKKU); Samsung Medical Center; National University of Singapore; Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; National University of Singapore; Universite Libre de Bruxelles
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2531197123
• 发表日期: 2026-03-17
• 页码: e2531197123
• 关键词: Mycobacterium abscessus; phage therapy; phage resistance; mycobacteriophage; morphotype; nontuberculous mycobacteria; BOLLETII; host; MASSILIENSE; PHAST

摘要

Mycobacterium abscessus infections represent a growing global health concern due to their severe pathology and difficulty of treatment, largely driven by their intrinsic antimicrobial resistance. While phage therapy has emerged as a promising alternative approach, studies have predominantly focused on glycopeptidolipids (GPL)-deficient M. abscessus rough variants instead of the GPL-producing smooth variants predominant in Asia. Here, we aim to develop phage cocktails targeting both smooth and rough morphotypes. In the process, we found that phage treatment of smooth variants can select for rough morphotype switching from smooth-to-rough variants in vitro and in vivo, resulting in phage resistance associated with mutations within the GPL biosynthetic locus. We validated our findings in vitro and in vivo, suggesting a two-layered phage combination that surpasses single-phage treatments and potentially improves clinical phage cocktail strategies. This work underlines the need to better understand mechanisms of phage resistance in phage therapy and associated potential adverse effects and solutions. Phage resistance in M. abscessus through morphotype switching is clinically significant, as it may complicate treatment outcomes but could be averted with proper phage combinations.