Iron-sulfur cluster delivery by SufT enables oxidative stress resistance and intracellular survival in Mycobacterium abscessus
Abstract
Non-tuberculous mycobacteria are emerging opportunistic pathogens, with Mycobacterium abscessus representing a major clinical challenge due to its intrinsic drug resistance, metabolic flexibility, and intracellular persistence. Iron–sulfur ([Fe–S]) clusters are essential cofactors for respiration, central metabolism, redox balance, and stress adaptation. In M. abscessus, the SUF system mediates [Fe–S] cluster assembly. Here, we show that M. abscessus SufT binds a [4Fe–4S] cluster, through an atypical coordination motif involving the unique Cys61, and transfers it to [Fe–S] enzymes such as aconitase. Deletion of sufT results in shortened bacilli, heightened susceptibility to oxidative stress, and profound lipidomic and metabolomic remodeling, including disruptions in TCA cycle, amino acid, nitrogen, cofactor, and membrane lipid metabolism. In addition, the ΔsufT mutant exhibits impaired energy production and decreased levels of structural phospholipids and cardiolipins. Importantly, SufT is required for efficient intracellular survival in macrophage-like THP-1 cells. The C61S substitution abolishes SufT-dependent [Fe–S] cluster transfer and impairs SufTdependent growth and intracellular proliferation, while preserving oxidative stress resistance. Collectively, these findings establish SufT as a central determinant of [Fe–S] cluster biogenesis, metabolic homeostasis, and oxidative stress resistance in M. abscessus, revealing a new site of vulnerability in this highly drug-resistant pathogen and highlighting [Fe–S] pathways as potential therapeutic targets.
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BibTeX
@article{berdal2026ironsulfur,
title = {{Iron-sulfur cluster delivery by SufT enables oxidative stress resistance and intracellular survival in Mycobacterium abscessus}},
author = {Valentin Berdal and Dorian Baude and Zhuoyan Chen and Bernhard Drotleff and Martin Clémancey and Chloé Deflandre and Yohann Duverger and Shriya Singh and Eva Todorovska and Gerald Larrouy-Maumus and Béatrice Py and Geneviève Blondin and Laurent Kremer and Sandrine Ollagnier de Choudens and Wassim Daher},
journal = {Current Research in Microbial Sciences},
year = {2026},
month = nov,
url = {https://hal.science/hal-05852262v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Iron-sulfur cluster delivery by SufT enables oxidative stress resistance and intracellular survival in Mycobacterium abscessus
AU - Valentin Berdal
AU - Dorian Baude
AU - Zhuoyan Chen
AU - Bernhard Drotleff
AU - Martin Clémancey
AU - Chloé Deflandre
AU - Yohann Duverger
AU - Shriya Singh
AU - Eva Todorovska
AU - Gerald Larrouy-Maumus
AU - Béatrice Py
AU - Geneviève Blondin
AU - Laurent Kremer
AU - Sandrine Ollagnier de Choudens
AU - Wassim Daher
PY - 2026
DA - 2026/11/04
JO - Current Research in Microbial Sciences
UR - https://hal.science/hal-05852262v1
AB - Non-tuberculous mycobacteria are emerging opportunistic pathogens, with Mycobacterium abscessus representing a major clinical challenge due to its intrinsic drug resistance, metabolic flexibility, and intracellular persistence. Iron–sulfur ([Fe–S]) clusters are essential cofactors for respiration, central metabolism, redox balance, and stress adaptation. In M. abscessus, the SUF system mediates [Fe–S] cluster assembly. Here, we show that M. abscessus SufT binds a [4Fe–4S] cluster, through an atypical coordination motif involving the unique Cys61, and transfers it to [Fe–S] enzymes such as aconitase. Deletion of sufT results in shortened bacilli, heightened susceptibility to oxidative stress, and profound lipidomic and metabolomic remodeling, including disruptions in TCA cycle, amino acid, nitrogen, cofactor, and membrane lipid metabolism. In addition, the ΔsufT mutant exhibits impaired energy production and decreased levels of structural phospholipids and cardiolipins. Importantly, SufT is required for efficient intracellular survival in macrophage-like THP-1 cells. The C61S substitution abolishes SufT-dependent [Fe–S] cluster transfer and impairs SufTdependent growth and intracellular proliferation, while preserving oxidative stress resistance. Collectively, these findings establish SufT as a central determinant of [Fe–S] cluster biogenesis, metabolic homeostasis, and oxidative stress resistance in M. abscessus, revealing a new site of vulnerability in this highly drug-resistant pathogen and highlighting [Fe–S] pathways as potential therapeutic targets.
SN - 2666-5174
ER -