Natural Product Type III Secretion System Inhibitors

Many known inhibitors of the bacterial type III secretion system (T3SS), a virulence factor used by pathogenic bacteria to infect host cells, are natural products. These compounds, produced by bacteria, fungi, and plants, may have developed as prophylactic treatments for potential attack by bacterial pathogens or as an attempt by symbiotic organisms to protect their hosts. Regardless, better understanding of the structures and mechanisms of action of these compounds may open opportunities for drug development against diseases caused by pathogens utilizing the T3SS. This review will cover selected known natural products of the T3SS and detail what is known of their origin and mechanism of action. These inhibitors highlight nature’s ability to modulate interactions between organisms at a cellular level.

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TRAPPC13 is a Novel Target of Mesorhizobium amorphae Type III Secretion System Effector NopP

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-12-20-0354-fi ◽

2021 ◽

Author(s):

Dongying Liu ◽

Yantao Luo ◽

Xiaofeng Zheng ◽

Xinye Wang ◽

Minxia Chou ◽

...

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Nitrogenase Activity ◽

Type Iii Secretion System ◽

Secretion System ◽

Host Cells ◽

Bimolecular Fluorescence Complementation ◽

Physical Interaction ◽

Type Iii ◽

Early Stages

Similar to pathogenic bacteria, rhizobia can inject effector proteins into host cells directly to promote infection via the type III secretion system. Nodulation outer protein P (NopP), a specific type III secretion system effector of rhizobia, plays different roles in the establishment of multiple rhizobia-legume symbiotic systems. Mesorhizobium amorphae CCNWGS0123 (GS0123), which infects Robinia pseudoacacia specifically, secretes several type III secretion system (T3SS) effectors, including NopP. Here, we demonstrate that NopP is secreted through T3SS-Ⅰof GS0123 during the early stages of infection, and its deficiency decreases nodule nitrogenase activity of R. pseudoacacia nodules. A trafficking protein particle complex subunit 13-like protein (TRAPPC13) ishas been identified as a NopP target protein in R. pseudoacacia roots by screening a yeast two-hybrid library. The physical interaction between NopP and TRAPPC13 is verified by bimolecular fluorescence complementation and co-immunoprecipitation assays. In addition, subcellular localization analysis reveals that both NopP and its target, TRAPPC13, are co-localized on the plasma membrane. Compared with GS0123-inoculated R. pseudoacacia roots, some genes associated with cell wall remodeling and plant innate immunity down-regulated in ΔnopP-inoculated roots at 36 hpi. The results suggest that NopP in M. amorphae CCNWGS0123 acts in multiple process in R. pseudoacacia during the early stages of infection, and TRAPPC13 could participate in the process as a NopP target.

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Antibodies Inhibiting the Type III Secretion System of Gram-Negative Pathogenic Bacteria

Antibodies ◽

10.3390/antib9030035 ◽

2020 ◽

Vol 9 (3) ◽

pp. 35

Author(s):

Julia A. Hotinger ◽

Aaron E. May

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

The United States ◽

Secretion System ◽

Effector Proteins ◽

Host Cells ◽

Gram Negative ◽

Type Iii ◽

Shigella Spp

Pathogenic bacteria are a global health threat, with over 2 million infections caused by Gram-negative bacteria every year in the United States. This problem is exacerbated by the increase in resistance to common antibiotics that are routinely used to treat these infections, creating an urgent need for innovative ways to treat and prevent virulence caused by these pathogens. Many Gram-negative pathogenic bacteria use a type III secretion system (T3SS) to inject toxins and other effector proteins directly into host cells. The T3SS has become a popular anti-virulence target because it is required for pathogenesis and knockouts have attenuated virulence. It is also not required for survival, which should result in less selective pressure for resistance formation against T3SS inhibitors. In this review, we will highlight selected examples of direct antibody immunizations and the use of antibodies in immunotherapy treatments that target the bacterial T3SS. These examples include antibodies targeting the T3SS of Pseudomonas aeruginosa, Yersinia pestis, Escherichia coli, Salmonella enterica, Shigella spp., and Chlamydia trachomatis.

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Innovation and Application of the Type III Secretion System Inhibitors in Plant Pathogenic Bacteria

Microorganisms ◽

10.3390/microorganisms8121956 ◽

2020 ◽

Vol 8 (12) ◽

pp. 1956

Author(s):

Xiaochen Yuan ◽

Manda Yu ◽

Ching-Hong Yang

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Plant Pathogens ◽

Current Knowledge ◽

Type Iii Secretion System ◽

Transcriptional Regulators ◽

Secretion System ◽

Plant Diseases ◽

Host Cells ◽

Type Iii

Many Gram-negative pathogenic bacteria rely on a functional type III secretion system (T3SS), which injects multiple effector proteins into eukaryotic host cells, for their pathogenicity. Genetic studies conducted in different host-microbe pathosystems often revealed a sophisticated regulatory mechanism of their T3SSs, suggesting that the expression of T3SS is tightly controlled and constantly monitored by bacteria in response to the ever-changing host environment. Therefore, it is critical to understand the regulation of T3SS in pathogenic bacteria for successful disease management. This review focuses on a model plant pathogen, Dickeyadadantii, and summarizes the current knowledge of its T3SS regulation. We highlight the roles of several T3SS regulators that were recently discovered, including the transcriptional regulators: FlhDC, RpoS, and SlyA; the post-transcriptional regulators: PNPase, Hfq with its dependent sRNA ArcZ, and the RsmA/B system; and the bacterial second messenger cyclic-di-GMP (c-di-GMP). Homologs of these regulatory components have also been characterized in almost all major bacterial plant pathogens like Erwiniaamylovora, Pseudomonassyringae, Pectobacterium spp., Xanthomonas spp., and Ralstonia spp. The second half of this review shifts focus to an in-depth discussion of the innovation and development of T3SS inhibitors, small molecules that inhibit T3SSs, in the field of plant pathology. This includes T3SS inhibitors that are derived from plant phenolic compounds, plant coumarins, and salicylidene acylhydrazides. We also discuss their modes of action in bacteria and application for controlling plant diseases.

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Bacterial Type III Secretion System Effector Proteins are Distinct between Plant Symbiotic, Plant Pathogenic and Animal Pathogenic Bacteria

IPSJ Transactions on Bioinformatics ◽

10.2197/ipsjtbio.7.2 ◽

2014 ◽

Vol 7 (0) ◽

pp. 2-15 ◽

Cited By ~ 1

Author(s):

Yuuichi Nakano ◽

Mitsuo Iwadate ◽

Hideaki Umeyama ◽

Y-h. Taguchi

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Secretion System ◽

Effector Proteins ◽

Type Iii ◽

Bacterial Type

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Regulation of the Type III Secretion System in Phytopathogenic Bacteria

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-19-1159 ◽

2006 ◽

Vol 19 (11) ◽

pp. 1159-1166 ◽

Cited By ~ 134

Author(s):

Xiaoyan Tang ◽

Yanmei Xiao ◽

Jian-Min Zhou

Keyword(s):

Signal Transduction ◽

Hypersensitive Response ◽

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Secretion System ◽

Host Cells ◽

Plant Pathogenic Bacteria ◽

Type Iii ◽

Hrp Genes

The type III secretion system (TTSS) is a specialized protein secretion machinery used by numerous gram-negative bacterial pathogens of animals and plants to deliver effector proteins directly into the host cells. In plant-pathogenic bacteria, genes encoding the TTSS were discovered as hypersensitive response and pathogenicity (hrp) genes, because mutation of these genes typically disrupts the bacterial ability to cause diseases on host plants and to elicit hypersensitive response on nonhost plants. The hrp genes and the type III effector genes (collectively called TTSS genes hereafter) are repressed in nutrient-rich media but induced when bacteria are infiltrated into plants or incubated in nutrient-deficient inducing media. Multiple regulatory components have been identified in the plant-pathogenic bacteria regulating TTSS genes under various conditions. In Ralstonia solanacearum, several signal transduction components essential for the induction of TTSS genes in plants are dispensable for the induction in inducing medium. In addition to the inducing signals, recent studies indicated the presence of negative signals in the plant regulating the Pseudomonas syringae TTSS genes. Thus, the levels of TTSS gene expression in plants likely are determined by the interactions of multiple signal transduction pathways. Studies of the hrp regulons indicated that TTSS genes are coordinately regulated with a number of non-TTSS genes.

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

Biomolecules ◽

10.3390/biom11020316 ◽

2021 ◽

Vol 11 (2) ◽

pp. 316 ◽

Cited By ~ 1

Author(s):

Julia A. Hotinger ◽

Heather A. Pendergrass ◽

Aaron E. May

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Systemic Infection ◽

Inhibitory Effect ◽

Secretion System ◽

Effector Proteins ◽

Host Cells ◽

Complex Nature ◽

Type Iii

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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An NF-κB-Based High-Throughput Screen Identifies Piericidins as Inhibitors of the Yersinia pseudotuberculosis Type III Secretion System

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02025-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 1118-1126 ◽

Cited By ~ 21

Author(s):

Miles C. Duncan ◽

Weng Ruh Wong ◽

Allison J. Dupzyk ◽

Walter M. Bray ◽

Roger G. Linington ◽

...

Keyword(s):

Natural Products ◽

Type Iii Secretion ◽

Mammalian Cells ◽

Yersinia Pseudotuberculosis ◽

Type Iii Secretion System ◽

Secretion System ◽

Host Cells ◽

Block Type ◽

Content Type ◽

Type Iii

ABSTRACTThe type III secretion system (T3SS) is a bacterial appendage used by dozens of Gram-negative pathogens to subvert host defenses and cause disease, making it an ideal target for pathogen-specific antimicrobials. Here, we report the discovery and initial characterization of two related natural products with T3SS-inhibitory activity that were derived from a marine actinobacterium. Bacterial extracts containing piericidin A1 and the piericidin derivative Mer-A 2026B inhibitedYersinia pseudotuberculosisfrom triggering T3SS-dependent activation of the host transcription factor NF-κB in HEK293T cells but were not toxic to mammalian cells. As theYersiniaT3SS must be functional in order to trigger NF-κB activation, these data indicate that piericidin A1 and Mer-A 2026B block T3SS function. Consistent with this, purified piericidin A1 and Mer-A 2026B dose-dependently inhibited translocation of theY. pseudotuberculosisT3SS effector protein YopM inside CHO cells. In contrast, neither compound perturbed bacterial growthin vitro, indicating that piericidin A1 and Mer-A 2026B do not function as general antibiotics inYersinia. In addition, whenYersiniawas incubated under T3SS-inducing culture conditions in the absence of host cells, Mer-A 2026B and piericidin A1 inhibited secretion of T3SS cargo as effectively as or better than several previously described T3SS inhibitors, such as MBX-1641 and aurodox. This suggests that Mer-A 2026B and piericidin A1 do not block type III secretion by blocking the bacterium-host cell interaction, but rather inhibit an earlier stage, such as T3SS needle assembly. In summary, the marine-derived natural products Mer-A 2026B and piericidin A1 possess previously uncharacterized activity against the bacterial T3SS.

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Process of Protein Transport by the Type III Secretion System

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.68.4.771-795.2004 ◽

2004 ◽

Vol 68 (4) ◽

pp. 771-795 ◽

Cited By ~ 276

Author(s):

Partho Ghosh

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Protein Transport ◽

Signal Sequence ◽

Type Iii Secretion System ◽

Secretion System ◽

Host Cells ◽

Inner Membrane ◽

Bacterial Flagellum ◽

Type Iii

SUMMARY The type III secretion system (TTSS) of gram-negative bacteria is responsible for delivering bacterial proteins, termed effectors, from the bacterial cytosol directly into the interior of host cells. The TTSS is expressed predominantly by pathogenic bacteria and is usually used to introduce deleterious effectors into host cells. While biochemical activities of effectors vary widely, the TTSS apparatus used to deliver these effectors is conserved and shows functional complementarity for secretion and translocation. This review focuses on proteins that constitute the TTSS apparatus and on mechanisms that guide effectors to the TTSS apparatus for transport. The TTSS apparatus includes predicted integral inner membrane proteins that are conserved widely across TTSSs and in the basal body of the bacterial flagellum. It also includes proteins that are specific to the TTSS and contribute to ring-like structures in the inner membrane and includes secretin family members that form ring-like structures in the outer membrane. Most prominently situated on these coaxial, membrane-embedded rings is a needle-like or pilus-like structure that is implicated as a conduit for effector translocation into host cells. A short region of mRNA sequence or protein sequence in effectors acts as a signal sequence, directing proteins for transport through the TTSS. Additionally, a number of effectors require the action of specific TTSS chaperones for efficient and physiologically meaningful translocation into host cells. Numerous models explaining how effectors are transported into host cells have been proposed, but understanding of this process is incomplete and this topic remains an active area of inquiry.

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