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The Type Three Secretion System of Pseudomonas aeruginosa as a Target for Development of Antivirulence Drugs

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Abstract

Pseudomonas aeruginosa is one of the leading antibiotic-resistant gram-negative organisms responsible for nosocomial infections. Multidrug pathogen resistance leads to the low antibiotic therapy efficiency. The solution for this problem involves developing new therapeutic agents that operate under different principles to the currently available antibiotics. The Type Three Secretion System (T3SS) is a major virulence factor in Pseudomonas aeruginosa. This review presents a brief description of structure and regulation of T3SS, which has been shown to contribute to the virulence of Gram-negative bacteria with different types of parasitism and is extremely necessary for the manifestation of the pathogenesis of diseases caused by them. The secretion apparatus is formed after bacteria contact with eukaryotic cell and allows the bacterium to inject toxins directly into the host cell cytoplasm. The T3SS regulation is a strictly hierarchically organized process that occurs at least at two levels, transcriptional and secretory. Thus, T3SS appears to be a highly attractive target for innovative therapies as it possesses a number of advantages over antibiotics: T3SS inhibitors are expected to have a lower risk of selecting resistance because they do not suppress the viability of pathogens, but only reduce bacterial virulence; inhibitors will be effective regardless of acquired antibiotic resistance; inhibitors will not to exert negligible effects on commensal bacteria. To date, a number of T3SS inhibitors with various nature and different mechanism of action have been identified. The discovered inhibitors suppress the transcription of the T3SS genes, toxins translocation and inhibit the effector molecules. For many of the developed inhibitors, their specific activity was shown in in vitro experiments, for few of them the antibacterial effect was shown in animal models and only two inhibitors are ongoing to test in clinical trials now: the Ftortiazinon and the antibodies MEDI3902.

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  1. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Moscow, Russia

    A. B. Sheremet, L. N. Nesterenko & N. A. Zigangirova

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  2. L. N. Nesterenko
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Sheremet A.B., е-mail: anna-pimenova@mail.ru; https://orcid.org/0000-0002-5210-5010

Nesterenko L.N., е-mail: nesterenko.mila@gmail.com; https://orcid.org/0000-0002-8893-5702

Zigangirova N.A., е-mail: zigangirova@mail.ru; https://orcid.org/0000-0001-6719-9403

Corresponding author: Sheremet A. B., е-mail: anna-pimenova@mail.ru

To cite this article:

Sheremet A.B., Nesterenko L.N., Zigangirova N.A. “The Pseudomonas aeruginosa Type-Three Secretion System as a Target for Development of Antivirulence Drugs.” Molekulyarnaya Genetika, Mikrobiologiya i Virusologiya (Molecular Genetics, Microbiology, and Virology), 2020, vol. 38, no. 1, pp. 3–14 (Russian). https://doi.org/10.17116/molgen2020380113

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Sheremet, A.B., Nesterenko, L.N. & Zigangirova, N.A. The Type Three Secretion System of Pseudomonas aeruginosa as a Target for Development of Antivirulence Drugs. Mol. Genet. Microbiol. Virol. 35, 1–13 (2020). https://doi.org/10.3103/S0891416820010073

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