Smooth-to-rough morphotype switching, a mechanism of phage resistance in <i> <i>Mycobacterium</i> abscessus </i>

<i><i>Mycobacterium</i> abscessus</i> 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 <i>M. abscessus</i> 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 <i>GPL</i> 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 <i>M. abscessus</i> through morphotype switching is clinically significant, as it may complicate treatment outcomes but could be averted with proper phage combinations.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-03-11
DOI
https://doi.org/10.1073/pnas.2531197123
Primary Topic
Bacteriophages and microbial interactions
Type
article
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article

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

Ria Sorayah, Wassim Daher, Kay En Low, J.Y. Richard Liew et al.
Proceedings of the National Academy of Sciences
Bacteriophages and microbial interactions
article

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

Ria Sorayah, Wassim Daher, Kay En Low, J.Y. Richard Liew, René Wintjens, Adeline Goulet, Morgane Illouz, Isabelle Bonne, Stefan H. Oehlers, Pablo Bifani, Roland G. Huber, Jeanette Teo, Claire Hamela, Kévin Pethe, Yan Sun, Lalit Mohan, Teck-Hui Teo, Byung Woo Jhun, Laurent Kremer, Chanvutha Ron, Aryeh Chiam, Riccardo Delli Ponti, Ayuni Norman, Renee Lew, Joanna Maw
article en

Abstract

<i><i>Mycobacterium</i> abscessus</i> 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 <i>M. abscessus</i> 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 <i>GPL</i> 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 <i>M. abscessus</i> through morphotype switching is clinically significant, as it may complicate treatment outcomes but could be averted with proper phage combinations.

Proceedings of the National Academy of SciencesVol. 123(11)
Agency for Science, Technology and Research (SG), Université Libre de Bruxelles (BE), Inserm (FR), National University of Singapore (SG), Nanyang Technological University (SG), Samsung Medical Center (KR), Institut de Microbiologie de la Méditerranée (FR), Institut de Recherche en Infectiologie de Montpellier (FR), National University Hospital (SG), Sungkyunkwan University (KR)
Openalex Percentile: Top 32%
Bacteriophages and microbial interactions
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