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EcoSal Plus

Domain 11: Antibiotic Mechanisms and Resistance

Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Alyssa C. Fasciano1, Lamyaa Shaban2, and Joan Mecsas3
  • Editors: Maria Sandkvist4, Eric Cascales5, Peter J. Christie6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111; 2: Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111; 3: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; 4: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; 5: CNRS Aix-Marseille Université, Mediterranean Institute of Microbiology, Marseille, France; 6: Department of Microbiology and Molecular Genetics, McGovern Medical School, Houston, Texas
  • Received 05 October 2018 Accepted 06 December 2018 Published 01 February 2019
  • Address correspondence to Joan Mecsas, [email protected]
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  • Abstract:

    Antibiotic resistance is a major public health threat that has stimulated the scientific community to search for nontraditional therapeutic targets. Because virulence, but not the growth, of many Gram-negative bacterial pathogens depends on the multicomponent type three secretion system injectisome (T3SSi), the T3SSi has been an attractive target for identifying small molecules, peptides, and monoclonal antibodies that inhibit its function to render the pathogen avirulent. While many small-molecule lead compounds have been identified in whole-cell-based high-throughput screens (HTSs), only a few protein targets of these compounds are known; such knowledge is an important step to developing more potent and specific inhibitors. Evaluation of the efficacy of compounds in animal studies is ongoing. Some efforts involving the development of antibodies and vaccines that target the T3SSi are further along and include an antibody that is currently in phase II clinical trials. Continued research into these antivirulence therapies, used alone or in combination with traditional antibiotics, requires combined efforts from both pharmaceutical companies and academic labs.

  • Citation: Fasciano A, Shaban L, Mecsas J. 2019. Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0032-2018

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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0032-2018
2019-02-01
2019-06-26

Abstract:

Antibiotic resistance is a major public health threat that has stimulated the scientific community to search for nontraditional therapeutic targets. Because virulence, but not the growth, of many Gram-negative bacterial pathogens depends on the multicomponent type three secretion system injectisome (T3SSi), the T3SSi has been an attractive target for identifying small molecules, peptides, and monoclonal antibodies that inhibit its function to render the pathogen avirulent. While many small-molecule lead compounds have been identified in whole-cell-based high-throughput screens (HTSs), only a few protein targets of these compounds are known; such knowledge is an important step to developing more potent and specific inhibitors. Evaluation of the efficacy of compounds in animal studies is ongoing. Some efforts involving the development of antibodies and vaccines that target the T3SSi are further along and include an antibody that is currently in phase II clinical trials. Continued research into these antivirulence therapies, used alone or in combination with traditional antibiotics, requires combined efforts from both pharmaceutical companies and academic labs.

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Figures

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Figure 1

Asterisks indicate regions with conserved components between T3SSi and flagella. Orange, ; blue, ; purple, EPEC/EHEC; green, ; red, . Potential targets of compounds based on inhibition of T3SSi function, biochemical or binding studies, genetic resistance, or animal studies.

Citation: Fasciano A, Shaban L, Mecsas J. 2019. Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0032-2018
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Tables

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Table 1

Possible targets and function of small-molecule inhibitors of the T3SS

Citation: Fasciano A, Shaban L, Mecsas J. 2019. Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0032-2018
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Table 2

Antibodies, vaccines, and peptomers against T3SS components

Citation: Fasciano A, Shaban L, Mecsas J. 2019. Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0032-2018

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