On the road to structure-based development of anti-virulence therapeutics targeting the type III secretion system injectisome

Lyons, Bronwyn; Strynadka, N.C.J.

doi:10.1039/c9md00146h

Cited by 19 publications

(22 citation statements)

References 141 publications

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“…The type III secretion system (T3SS) is a syringe-like multimembrane-spanning nanomachine that is often essential to the pathogenicity, but not viability, of many clinically relevant Gram-negative bacteria, such as enteropathogenic Escherichia coli (EPEC), Salmonella enterica, and Pseudomonas aeruginosa. The function of the T3SS in these pathogens is directly responsible for the downstream development of illnesses such as whooping cough, sexually transmitted chlamydial disease, and hospital-acquired pneumonia (Lyons and Strynadka, 2019). The T3SS forms a continuous channel from the bacterial cytosol into the eukaryotic host cell whereby proteinaceous virulence factors traverse, leading to the disruption of vital host cellular processes such as cytoskeletal arrangement, protein synthesis, and immune responses.…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the EspA filament from enteropathogenic Escherichia coli: Revealing the mechanism of effector translocation in the T3SS

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the EspA filament from enteropathogenic Escherichia coli: Revealing the mechanism of effector translocation in the T3SS

et al. 2021

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“…Although several antivirulence drugs are currently under various stages of development, (e.g. toxin, adhesin, enzyme, secretion and quorum sensing inhibitors 6 , 8 , 9 ) the potential of any antivirulence drug candidate for further clinical development relies on having established robust assays for evaluating their efficacy in vitro and in vivo 10 . While the development of antibiotics over the past several decades has benefited from standardised and comprehensive preclinical and clinical evaluation methods, the field of antivirulence drugs has had minimal guidelines for consistent testing, with only a few general guidelines reported for some types of inhibitors, e.g.…”

Section: Introductionmentioning

confidence: 99%

A high-throughput cell-based assay pipeline for the preclinical development of bacterial DsbA inhibitors as antivirulence therapeutics

Verderosa

Dhouib

Hong

et al. 2021

Sci Rep

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Antibiotics are failing fast, and the development pipeline remains alarmingly dry. New drug research and development is being urged by world health officials, with new antibacterials against multidrug-resistant Gram-negative pathogens as the highest priority. Antivirulence drugs, which inhibit bacterial pathogenicity factors, are a class of promising antibacterials, however, their development is stifled by lack of standardised preclinical testing akin to what guides antibiotic development. The lack of established target-specific microbiological assays amenable to high-throughput, often means that cell-based testing of virulence inhibitors is absent from the discovery (hit-to-lead) phase, only to be employed at later-stages of lead optimization. Here, we address this by establishing a pipeline of bacterial cell-based assays developed for the identification and early preclinical evaluation of DsbA inhibitors, previously identified by biophysical and biochemical assays. Inhibitors of DsbA block oxidative protein folding required for virulence factor folding in pathogens. Here we use existing Escherichia coli DsbA inhibitors and uropathogenic E. coli (UPEC) as a model pathogen, to demonstrate that the combination of a cell-based sulfotransferase assay and a motility assay (both DsbA reporter assays), modified for a higher throughput format, can provide a robust and target-specific platform for the identification and evaluation of DsbA inhibitors.

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“…Resistance to compounds targeting virulence factors will most likely not evolve and spread in endogenous bacterial flora, since these bacteria do not express the specific virulence targets. The T3SS of P. aeruginosa and other gram-negative pathogens have been explored as targets for the development of virulence-blocking antibacterial agents [ 30 , 31 ]. A number of synthetic and natural compounds have been demonstrated to block the T3SS of P. aeruginosa , resulting in attenuation of infection in vitro and in vivo [ 32 , 33 , 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Small Molecules Blocking the Pseudomonas aeruginosa Type III Secretion System Protein PcrV

Sundin¹,

Saleeb²,

Spjut³

et al. 2021

Biomolecules

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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.

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On the road to structure-based development of anti-virulence therapeutics targeting the type III secretion system injectisome

Abstract: Targeting the T3SS injectisome using the anti-virulence strategy offers an alternative to antibiotic therapeutic approaches when dealing with resistance.

Cited by 19 publications

References 141 publications

Cryo-EM structure of the EspA filament from enteropathogenic Escherichia coli: Revealing the mechanism of effector translocation in the T3SS

Cryo-EM structure of the EspA filament from enteropathogenic Escherichia coli: Revealing the mechanism of effector translocation in the T3SS

A high-throughput cell-based assay pipeline for the preclinical development of bacterial DsbA inhibitors as antivirulence therapeutics

Identification of Small Molecules Blocking the Pseudomonas aeruginosa Type III Secretion System Protein PcrV

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