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The expanding bacterial type IV secretion lexicon.

ABSTRACT: The bacterial type IV secretion systems (T4SSs) comprise a biologically diverse group of translocation systems functioning to deliver DNA or protein substrates from donor to target cells generally by a mechanism dependent on establishment of direct cell-to-cell contact. Members of one T4SS subfamily, the conjugation systems, mediate the widespread and rapid dissemination of antibiotic resistance and virulence traits among bacterial pathogens. Members of a second subfamily, the effector translocators, are used by often medically-important pathogens to deliver effector proteins to eukaryotic target cells during the course of infection. Here we summarize our current understanding of the structural and functional diversity of T4SSs and of the evolutionary processes shaping this diversity. We compare mechanistic and architectural features of T4SSs from Gram-negative and -positive species. Finally, we introduce the concept of the 'minimized' T4SSs; these are systems composed of a conserved set of 5-6 subunits that are distributed among many Gram-positive and some Gram-negative species.

SUBMITTER: Bhatty M

PROVIDER: S-EPMC3816095 | biostudies-literature | 2013 Jul-Aug

REPOSITORIES: biostudies-literature

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The expanding bacterial type IV secretion lexicon.

Bhatty Minny M Laverde Gomez Jenny A JA Christie Peter J PJ

Research in microbiology 20130328 6

The bacterial type IV secretion systems (T4SSs) comprise a biologically diverse group of translocation systems functioning to deliver DNA or protein substrates from donor to target cells generally by a mechanism dependent on establishment of direct cell-to-cell contact. Members of one T4SS subfamily, the conjugation systems, mediate the widespread and rapid dissemination of antibiotic resistance and virulence traits among bacterial pathogens. Members of a second subfamily, the effector transloca ...[more]

PMID: 23542405

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Project description:UnlabelledBacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs.ImportanceMany human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.

Dataset Information

The expanding bacterial type IV secretion lexicon.

Publications

The expanding bacterial type IV secretion lexicon.

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