Special Issue "Virulence Systems of Human Pathogens as Targets for Novel Therapeutics and Prophylactics"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2021).

Special Issue Editor

Dr. Wiesław Świętnicki
E-Mail Website
Guest Editor
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, Wroclaw, Poland
Interests: virulence systems; ATPases; inhibitors; vaccines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Bacterial pathogens have specialized protein transport systems used to secrete toxins and deliver them to their intended targets. In the case of human pathogens, the proteins are mostly toxins that are designed to interfere with the host cell’s metabolism and general functioning. The predominant targets are cells of the immune system, where many components have their function disabled or severely interrupted by the secreted bacterial toxins.

There are at least nine secretory systems known in pathogens, and each one is highly conserved in the organization and mechanism of protein transport. Since many are not necessary for the pathogen’s survival outside the host but necessary for the infection, the secretory systems have become a point of interest for indirect antibacterial strategies targeting the function of systems, their assembly, and the mechanism of protein transport. Surprisingly, solutions designed against one pathogen are effective against a broader range of bacteria, which suggests that the strategy may deliver broad-spectrum antibacterials. Since the mechanism is different than for known commercial vaccines and antibiotics, the indirect-acting agents may offer a strategy to break the drug resistance barrier.

As enticing as it is, the approach has some potential problems. The pathogens are not directly destroyed by the compounds/proteins and require a functioning immune system of the host to defeat the attacking pathogen. In many immunocompromised patients, most frequently with underlying conditions related to weakened or compromised immune systems, the strategy alone may not work and would require additional help from direct-acting agents such as antibiotics. Therefore, the indirect-acting agents may be relegated to a secondary role unless converted to direct-acting drugs in the future.

Dr. Wiesław Świętnicki
Guest Editor

Manuscript Submission Information

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Keywords

  • secretory systems
  • inhibitors
  • system assembly
  • protein transport
  • animal models for indirect-acting therapeutics
  • antibodies directed against the secretory systems
  • small molecules
  • structural components
  • secretory ATPases
  • human receptors for the toxins
  • in silico approaches to understanding the mechanism of toxicity and protein transport mechanism
  • human pathogens

Published Papers (3 papers)

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Research

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Article
Identification of Small Molecules Blocking the Pseudomonas aeruginosa Type III Secretion System Protein PcrV
Biomolecules 2021, 11(1), 55; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010055 - 04 Jan 2021
Cited by 2 | Viewed by 1179
Abstract
Pseudomonas aeruginosa is an opportunistic bacterial pathogen that employs its type III secretion system (T3SS) during the acute phase of infection to translocate cytotoxins into the host cell cytoplasm to evade the immune system. The PcrV protein is located at the tip of [...] Read more.
Pseudomonas aeruginosa is an opportunistic bacterial pathogen that employs its type III secretion system (T3SS) during the acute phase of infection to translocate cytotoxins into the host cell cytoplasm to evade the immune system. The PcrV protein is located at the tip of the T3SS, facilitates the integration of pore-forming proteins into the eukaryotic cell membrane, and is required for translocation of cytotoxins into the host cell. In this study, we used surface plasmon resonance screening to identify small molecule binders of PcrV. A follow-up structure-activity relationship analysis resulted in PcrV binders that protect macrophages in a P. aeruginosa cell-based infection assay. Treatment of P. aeruginosa infections is challenging due to acquired, intrinsic, and adaptive resistance in addition to a broad arsenal of virulence systems such as the T3SS. Virulence blocking molecules targeting PcrV constitute valuable starting points for development of next generation antibacterials to treat infections caused by P. aeruginosa. Full article
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Review

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Review
Secretory System Components as Potential Prophylactic Targets for Bacterial Pathogens
Biomolecules 2021, 11(6), 892; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060892 - 15 Jun 2021
Viewed by 1284
Abstract
Bacterial secretory systems are essential for virulence in human pathogens. The systems have become a target of alternative antibacterial strategies based on small molecules and antibodies. Strategies to use components of the systems to design prophylactics have been less publicized despite vaccines being [...] Read more.
Bacterial secretory systems are essential for virulence in human pathogens. The systems have become a target of alternative antibacterial strategies based on small molecules and antibodies. Strategies to use components of the systems to design prophylactics have been less publicized despite vaccines being the preferred solution to dealing with bacterial infections. In the current review, strategies to design vaccines against selected pathogens are presented and connected to the biology of the system. The examples are given for Y. pestis, S. enterica, B. anthracis, S. flexneri, and other human pathogens, and discussed in terms of effectiveness and long-term protection. Full article
Review
Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components
Biomolecules 2021, 11(2), 316; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11020316 - 19 Feb 2021
Cited by 3 | Viewed by 1500
Abstract
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 [...] Read more.
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. Full article
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