Discovery and Mechanism of Type III Secretion System Inhibitors

May, Aaron E.; Khosla, Chaitan

doi:10.1002/ijch.201300025

Cited by 4 publications

(6 citation statements)

References 81 publications

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“…The T3SS is responsible for the secretion of effector proteins, and their expression can be correlated to T3SS function and inhibition [11,44,45]. Many T3SS inhibitors have been discovered using in vitro secretion assays [33]. These assays are typically performed by monitoring effector protein release into the supernatant.…”

Section: Virulence Expression/effector Secretion Assaysmentioning

confidence: 99%

“…The T3SS is an attractive anti-virulence target, because many T3SS knockout strains have attenuated virulence [12,[22][23][24][25][26][27][28][29][30][31]. Efforts have gone into screening for T3SS inhibitors, and a common theme among them is a lack of toxicity to the pathogen [22,32,33]. This is an important feature of these inhibitors, because it means they do not exert selective pressure.…”

Section: Introductionmentioning

confidence: 99%

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Animal Models of Type III Secretion System-Mediated Pathogenesis

Hotinger

May

2019

Pathogens

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The type III secretion system (T3SS) is a conserved virulence factor used by many Gram-negative pathogenic bacteria and has become an important target for anti-virulence drugs. Most T3SS inhibitors to date have been discovered using in vitro screening assays. Pharmacokinetics and other important characteristics of pharmaceuticals cannot be determined with in vitro assays alone. In vivo assays are required to study pathogens in their natural environment and are an important step in the development of new drugs and vaccines. Animal models are also required to understand whether T3SS inhibition will enable the host to clear the infection. This review covers selected animal models (mouse, rat, guinea pig, rabbit, cat, dog, pig, cattle, primates, chicken, zebrafish, nematode, wax moth, flea, fly, and amoeba), where T3SS activity and infectivity have been studied in relation to specific pathogens (Escherichia coli, Salmonella spp., Pseudomonas spp., Shigella spp., Bordetella spp., Vibrio spp., Chlamydia spp., and Yersinia spp.). These assays may be appropriate for those researching T3SS inhibition.

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Section: Virulence Expression/effector Secretion Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Animal Models of Type III Secretion System-Mediated Pathogenesis

Hotinger

May

2019

Pathogens

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“…Enzyme or analyte secretion are common methods for monitoring T3SS activity. These methods can be used for the identification of inhibitors of the T3SS [31,[70][71][72][73]. In both cases of translocation into a host cell and secretion into extracellular space, the correct folding of the enzyme being secreted is important and must be considered.…”

Section: Enzyme and Analyte Secretion For Monitoring T3ss Activitymentioning

confidence: 99%

“…This section will review a few established methods for analyzing T3SS activity using enzyme or analyte secretion. Many reviews exist that provide more information on specific inhibitors analyzed in vitro [25,72,73].…”

Section: Enzyme and Analyte Secretion For Monitoring T3ss Activitymentioning

confidence: 99%

Delivery of Heterologous Proteins, Enzymes, and Antigens via the Bacterial Type III Secretion System

Pendergrass

May

2020

Microorganisms

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The Type III Secretion System (T3SS) is a multimeric protein complex composed of over 20 different proteins, utilized by Gram-negative bacteria to infect eukaryotic host cells. The T3SS has been implicated as a virulence factor by which pathogens cause infection and has recently been characterized as a communication tool between bacteria and plant cells in the rhizosphere. The T3SS has been repurposed to be used as a tool for the delivery of non-native or heterologous proteins to eukaryotic cells or the extracellular space for a variety of purposes, including drug discovery and drug delivery. This review covers the methodology of heterologous protein secretion as well as multiple cases of utilizing the T3SS to deliver heterologous proteins or artificial materials. The research covered in this review will serve to outline the scope and limitations of utilizing the T3SS as a tool for protein delivery.

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“…With this in mind, a general T3SS inhibitor may prevent the motility of commensal bacteria, resulting in a loss of many benefits to a pathogen-specific treatment. A common theme among T3SS inhibitor screening assays is a lack of toxicity to the pathogen [ 51 , 52 ]. This means the inhibitors do not exert selective pressure, potentially reducing the rate of resistance formation to these agents [ 53 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

2021

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The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing a T3SS are responsible for millions of infections yearly. Since many T3SS knockout strains are incapable of causing systemic infection, the T3SS has emerged as an attractive anti-virulence target for therapeutic design. The T3SS is a multiprotein molecular syringe that enables pathogens to inject effector proteins into host cells. These effectors modify host cell mechanisms in a variety of ways beneficial to the pathogen. Due to the T3SS’s complex nature, there are numerous ways in which it can be targeted. This review will be focused on the direct targeting of components of the T3SS, including the needle, translocon, basal body, sorting platform, and effector proteins. Inhibitors will be considered a direct inhibitor if they have a binding partner that is a T3SS component, regardless of the inhibitory effect being structural or functional.

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Discovery and Mechanism of Type III Secretion System Inhibitors

Cited by 4 publications

References 81 publications

Animal Models of Type III Secretion System-Mediated Pathogenesis

Animal Models of Type III Secretion System-Mediated Pathogenesis

Delivery of Heterologous Proteins, Enzymes, and Antigens via the Bacterial Type III Secretion System

Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

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