Smooth-to-rough morphotype switching, a mechanism of phage resistance in <i> <i>Mycobacterium</i> abscessus </i>
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Jun Hao Liew
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13
Ayuni Norman
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13
Morgane Illouz
Centre National de la Recherche Scientifique, UMR 9004, Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier
Teck-Hui Teo
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13
Riccardo Delli Ponti
A*STAR Bioinformatics Institute, Agency for Science, Technology and Research
Claire Hamela
Lalit Mohan
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13
Renee Lew
Lee Kong Chian School of Medicine, Experimental Medicine Building, Nanyang Technological University
Chanvutha Ron
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13
Kay En Low
Electron Microscopy Unit, Microscopy Cluster, Yong Loo Lin School of Medicine, National University of Singapore
Wassim Daher
Centre National de la Recherche Scientifique, UMR 9004, Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier
Aryeh Chiam
A*STAR Bioinformatics Institute, Agency for Science, Technology and Research
Joanna Maw
Lee Kong Chian School of Medicine, Experimental Medicine Building, Nanyang Technological University
Yan Sun
Ria Sorayah
Lee Kong Chian School of Medicine, Experimental Medicine Building, Nanyang Technological University
Stefan H. Oehlers
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13
Byung Woo Jhun
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
Jeanette W. P. Teo
Department of Laboratory Medicine, National University Hospital
Adeline Goulet
Isabelle Bonne
Electron Microscopy Unit, Microscopy Cluster, Yong Loo Lin School of Medicine, National University of Singapore
René Wintjens
Kevin Pethe
Roland G. Huber
A*STAR Bioinformatics Institute, Agency for Science, Technology and Research
Laurent Kremer
Pablo Bifani
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos #05-13