Dataset Information

Essential Staphylococcus aureus toxin export system.

ABSTRACT: Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection. Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis and have a major impact on the ability of highly virulent S. aureus to cause disease. However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here we report that an ATP-binding cassette transporter with previously unknown function is responsible for the export of all PSMs, thus representing a single target for complete obstruction of PSM production. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the extent of its effect on the development of S. aureus infection was similar to that of the sum of all PSMs. Notably, the transporter was essential for bacterial growth. Furthermore, it contributed to producer immunity toward secreted PSMs and defense against PSM-mediated bacterial interference. Our study reveals a noncanonical, dedicated secretion mechanism for an important class of toxins and identifies this mechanism as a comprehensive potential target for the development of drugs to efficiently inhibit the growth and virulence of pathogenic staphylococci.

SUBMITTER: Chatterjee SS

PROVIDER: S-EPMC3594369 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Essential Staphylococcus aureus toxin export system.

Chatterjee Som S SS Joo Hwang-Soo HS Duong Anthony C AC Dieringer Thomas D TD Tan Vee Y VY Song Yan Y Fischer Elizabeth R ER Cheung Gordon Y C GY Li Min M Otto Michael M

Nature medicine 20130210 3

Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection. Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis and have a major impact on the ability of highly virulent S. aureus to cause disease. However, targeting PSMs for therapeutic intervention is ...[more]

PMID: 23396209

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Project description:Bacterial cells respond to environmental stresses by modulating their gene expression and adjusting their proteome. In Staphylococcus aureus, selective degradation by ClpP protease eliminates damaged proteins and regulates the abundance of functional proteins such as many important stress-induced transcriptional regulators. Degradation by ClpP requires the unfolding activity of partner Clp ATPases, such as ClpX and ClpC, and assistance of substrate-specific adaptor proteins such as YjbH and TrfA. Herein, we demonstrated that YjbH is aggregated in response to growth stress stimuli, such as oxidative and antibiotic stresses. In consequence, its function as an adaptor protein is compromised. YjbH controls the degradation of the stress-induced transcriptional regulator, Spx. Aggregated YjbH cannot assist Spx degradation, which results in Spx accumulation. We discovered that depending on the stress stimulus, Spx can be soluble or insoluble, and, consequently, transcriptionally active or inactive. Therefore, Spx accumulation and solubility are key components governing activation of Spx-dependent genes. Spx positively regulates expression of a ClpCP adaptor protein TrfA. TrfA in turn is required for degradation of MazE antitoxin, the unstable component of the MazEF toxin-antitoxin system, that neutralizes the endoribonuclease activity of MazF toxin. Bacterial toxin-antitoxin systems are associated with dormancy and tolerance to antibiotics that are related to chronic and relapsing infections, and it is at present a key unresolved problem in medicine. MazF activity was linked to growth stasis, yet the precise environmental signals that trigger MazE degradation and MazF activation are poorly understood. Here we propose a model where YjbH serves as a sensor of environmental stresses for downstream regulation of MazEF activity. YjbH aggregation, soluble Spx, and TrfA, coordinately control MazE antitoxin levels and consequently MazF toxin activity. This model implies that certain stress conditions culminate in modulation of MazF activity resulting in growth stasis during in vivo infections.

Dataset Information

Essential Staphylococcus aureus toxin export system.

Publications

Essential Staphylococcus aureus toxin export system.

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