The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility
- 1School of Public Health, University at Albany, Albany, New York, United States of America
- 2Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America
Abstract
A major determinant of the exceptional intrinsic resistance of M. abscessus is the lipid-rich cell envelope, yet the regulatory systems that remodel envelope-associated pathways remain poorly defined. Here, we determine the σD regulon in M. abscessus and establish its role in cell envelope homeostasis and intrinsic resistance to hydrophobic antibiotics. RNA-Seq analysis of a MabΔsigD mutant identified 447 differentially expressed genes, while ChIP-Seq mapped 72 σD binding sites and defined a conserved promoter motif (GTAACA/G-N16-CGAT). Using a combination of σD binding, motif orientation and expression data, we identified a core set of directly regulated genes, distinct from what was previously observed in M. tuberculosis, many of which encode proteins involved in envelope-associated functions. These include loci involved in trehalose polyphleate (TPP) biosynthesis, the antigen 85 complex and peptidoglycan remodeling enzymes. Deletion of sigD resulted in a significant reduction in TPPs in the cell envelope and an increase in ethidium bromide accumulation. Consistent with these changes, loss of σD selectively sensitized M. abscessus to hydrophobic antibiotics, including rifampicin and tigecycline. Deletion of mmpL10, which is required for transport of TPP precursors, recapitulated the drug sensitivity of MabΔsigD, implicating envelope composition as a key effector of the phenotype. Expression of the σD regulon further increased during starvation and in response to SDS, isoniazid, and ethambutol, mediated by degradation of RsdA, consistent with a role in stress-responsive envelope adaptation. Together, these findings demonstrate σD is active during logarithmic growth in rich media where it regulates the expression of envelope-associated genes that influence envelope permeability and basal level susceptibility to hydrophobic antibiotics; its activity further increases in response to cell envelope stress, presumably promoting envelope remodeling to counteract damage. Author summary: Mycobacterium abscessus is an increasingly important bacterial pathogen that causes difficult-to-treat infections because it is naturally resistant to many antibiotics. A major contributor to this resistance is its complex, lipid-rich cell envelope, which acts as a barrier that limits the entry of antibiotics. How this protective barrier is regulated and remodeled in response to environmental stress is not well understood. Here, we investigated the role of the alternative sigma factor D (σD), a protein that controls the expression of specific groups of genes. We found that σD regulates numerous genes associated with the bacterial cell envelope, including genes involved in the production and transport of specialized surface lipids. Loss of σD altered the abundance of trehalose polyphleates and made bacteria more susceptible to several hydrophobic antibiotics. We further found that σD activity increases during nutrient starvation and when the cell envelope is disrupted. Our findings identify σD as part of a regulatory network that helps maintain the Mycobacterium abscessus cell envelope and influences its intrinsic resistance to antibiotics.
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BibTeX
@article{jones2026sigd,
title = {{The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility}},
author = {Sean R. Jones and Kelly Maune and Kelley Hurst-Hess and Pallavi Ghosh},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012286},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012286},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility
AU - Sean R. Jones
AU - Kelly Maune
AU - Kelley Hurst-Hess
AU - Pallavi Ghosh
PY - 2026
DA - 2026/09/02
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012286
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012286
AB - A major determinant of the exceptional intrinsic resistance of M. abscessus is the lipid-rich cell envelope, yet the regulatory systems that remodel envelope-associated pathways remain poorly defined. Here, we determine the σD regulon in M. abscessus and establish its role in cell envelope homeostasis and intrinsic resistance to hydrophobic antibiotics. RNA-Seq analysis of a MabΔsigD mutant identified 447 differentially expressed genes, while ChIP-Seq mapped 72 σD binding sites and defined a conserved promoter motif (GTAACA/G-N16-CGAT). Using a combination of σD binding, motif orientation and expression data, we identified a core set of directly regulated genes, distinct from what was previously observed in M. tuberculosis, many of which encode proteins involved in envelope-associated functions. These include loci involved in trehalose polyphleate (TPP) biosynthesis, the antigen 85 complex and peptidoglycan remodeling enzymes. Deletion of sigD resulted in a significant reduction in TPPs in the cell envelope and an increase in ethidium bromide accumulation. Consistent with these changes, loss of σD selectively sensitized M. abscessus to hydrophobic antibiotics, including rifampicin and tigecycline. Deletion of mmpL10, which is required for transport of TPP precursors, recapitulated the drug sensitivity of MabΔsigD, implicating envelope composition as a key effector of the phenotype. Expression of the σD regulon further increased during starvation and in response to SDS, isoniazid, and ethambutol, mediated by degradation of RsdA, consistent with a role in stress-responsive envelope adaptation. Together, these findings demonstrate σD is active during logarithmic growth in rich media where it regulates the expression of envelope-associated genes that influence envelope permeability and basal level susceptibility to hydrophobic antibiotics; its activity further increases in response to cell envelope stress, presumably promoting envelope remodeling to counteract damage. Author summary: Mycobacterium abscessus is an increasingly important bacterial pathogen that causes difficult-to-treat infections because it is naturally resistant to many antibiotics. A major contributor to this resistance is its complex, lipid-rich cell envelope, which acts as a barrier that limits the entry of antibiotics. How this protective barrier is regulated and remodeled in response to environmental stress is not well understood. Here, we investigated the role of the alternative sigma factor D (σD), a protein that controls the expression of specific groups of genes. We found that σD regulates numerous genes associated with the bacterial cell envelope, including genes involved in the production and transport of specialized surface lipids. Loss of σD altered the abundance of trehalose polyphleates and made bacteria more susceptible to several hydrophobic antibiotics. We further found that σD activity increases during nutrient starvation and when the cell envelope is disrupted. Our findings identify σD as part of a regulatory network that helps maintain the Mycobacterium abscessus cell envelope and influences its intrinsic resistance to antibiotics.
SN - 1553-7404
ER -