Targeting the type III secretion system to treat bacterial infections

Marshall, Natalie C.; Finlay, B. Brett

doi:10.1517/14728222.2014.855199

Cited by 61 publications

(57 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(Coburn et al, 2007b;Troisfontaines and Cornelis, 2005). This renders the T3SS a very attractive target for the development of new antibiotics and vaccines (Keyser et al, 2008;Kline et al, 2012;Marshall and Finlay, 2014).…”

Section: Introductionmentioning

confidence: 99%

The Modular Structure of the Inner-Membrane Ring Component PrgK Facilitates Assembly of the Type III Secretion System Basal Body

Bergeron

Worrall

et al. 2015

Structure

View full text Add to dashboard Cite

The type III secretion system (T3SS) is a large macromolecular assembly found at the surface of many pathogenic Gram-negative bacteria. Its role is to inject toxic "effector" proteins into the cells of infected organisms. The molecular details of the assembly of this large, multimembrane-spanning complex remain poorly understood. Here, we report structural, biochemical, and functional analyses of PrgK, an inner-membrane component of the prototypical Salmonella typhimurium T3SS. We have obtained the atomic structures of the two ring building globular domains and show that the C-terminal transmembrane helix is not essential for assembly and secretion. We also demonstrate that structural rearrangement of the two PrgK globular domains, driven by an interconnecting linker region, may promote oligomerization into ring structures. Finally, we used electron microscopy-guided symmetry modeling to propose a structural model for the intimately associated PrgH-PrgK ring interaction within the assembled basal body.

show abstract

Section: Introductionmentioning

confidence: 99%

The Modular Structure of the Inner-Membrane Ring Component PrgK Facilitates Assembly of the Type III Secretion System Basal Body

Bergeron

Worrall

et al. 2015

Structure

View full text Add to dashboard Cite

show abstract

“…3). The fact that the T3SS is the most conserved secretion system amongst the classical bordetellae confirms the significant role of this system in the many shared characteristics of these common and successful mammalian respiratory pathogens (Marshall & Finlay, 2014). Some of the variations observed in other secretion systems are likely to contribute to the known phenotypic differences amongst these species.…”

Section: Discussionmentioning

confidence: 81%

Diversity of secretion systems associated with virulence characteristics of the classical bordetellae

et al. 2015

View full text Add to dashboard Cite

“…The TTSS of pathogenic bacteria is considered a promising target for the development of anti-infection therapeutics because it is highly conserved in structure and function and has an essential role in virulence (39)(40)(41). Alternative treatment strate- pseudomallei K96243 wild type () or the bsaS deletion mutant (OE) was determined (n ϭ 7 per group).…”

Section: Secretion Of the Ttss3 Effector Bope Is Blocked By Treatmentmentioning

confidence: 99%

“…gies are required urgently for many TTSS-containing pathogens, since many, including B. pseudomallei, have developed resistance to multiple antibiotics. Over the last decade many natural product and synthetic compound inhibitors targeting bacterial TTSS have been identified by high-throughput screening or rational design methods (39)(40)(41). However, in the majority of cases the TTSS component targeted by the inhibitor remains unknown, and thus very few have been fully investigated for their mechanism of action (42).…”

Section: Secretion Of the Ttss3 Effector Bope Is Blocked By Treatmentmentioning

confidence: 99%

Burkholderia pseudomallei Type III Secretion System Cluster 3 ATPase BsaS, a Chemotherapeutic Target for Small-Molecule ATPase Inhibitors

et al. 2015

View full text Add to dashboard Cite

Melioidosis is an infectious disease of high mortality for humans and other animal species; it is prevalent in tropical regions worldwide. The pathogenesis of melioidosis depends on the ability of its causative agent, the Gram-negative bacterium Burkholderia pseudomallei, to enter and survive in host cells. B. pseudomallei can escape from the phagosome into the cytosol of phagocytic cells where it replicates and acquires actin-mediated motility, avoiding killing by the autophagy-dependent process, LC3 (microtubule-associated protein light chain 3)-associated phagocytosis (LAP). The type III secretion system cluster 3 (TTSS3) facilitates bacterial escape from phagosomes, although the mechanism has not been fully elucidated. Given the recent identification of small-molecule inhibitors of the TTSS ATPase, we sought to determine the potential of the predicted TTSS3 ATPase, encoded by bsaS, as a target for chemotherapeutic treatment of infection. A B. pseudomallei bsaS deletion mutant was generated and used as a control against which to assess the effect of inhibitor treatment. Infection of RAW 264.7 cells with wildtype bacteria and subsequent treatment with the ATPase inhibitor compound 939 resulted in reduced intracellular bacterial survival, reduced escape from phagosomes, and increased colocalization with both LC3 and the lysosomal marker LAMP1 (lysosome-associated membrane protein 1). These changes were similar to those observed for infection of RAW 264.7 cells with the bsaS deletion mutant. We propose that treatment with the ATPase inhibitor compound 939 decreased intracellular bacterial survival through a reduced ability of bacteria to escape from phagosomes and increased killing via LAP. Therefore, small-molecule inhibitors of the TTSS3 ATPase have potential as therapeutic treatments against melioidosis.

show abstract

Targeting the type III secretion system to treat bacterial infections

Cited by 61 publications

References 105 publications

The Modular Structure of the Inner-Membrane Ring Component PrgK Facilitates Assembly of the Type III Secretion System Basal Body

The Modular Structure of the Inner-Membrane Ring Component PrgK Facilitates Assembly of the Type III Secretion System Basal Body

Diversity of secretion systems associated with virulence characteristics of the classical bordetellae

Burkholderia pseudomallei Type III Secretion System Cluster 3 ATPase BsaS, a Chemotherapeutic Target for Small-Molecule ATPase Inhibitors

Contact Info

Product

Resources

About