N-Hydroxybenzimidazole inhibitors of ExsA MAR transcription factor in Pseudomonas aeruginosa: In vitro anti-virulence activity and metabolic stability

Grier, Mark C.; Garrity-Ryan, Lynne; Bartlett, Victoria J.; Klausner, Kevin A.; Donovan, Peter; Dudley, Caroline; Alekshun, Michael N.; Tanaka, Sébastien; Draper, Michael P.; Levy, Stuart B.; Kim, Oak K.

doi:10.1016/j.bmcl.2010.04.014

Cited by 34 publications

(38 citation statements)

References 12 publications

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“…These results validate the P. aeruginosa T3SS as an important target for therapeutic and/or prophylactic intervention. Indeed, several inhibitors of P. aeruginosa T3SS have been described, both small molecules (12)(13)(14)(15)(16) and monoclonal antibodies (17,18). The most advanced of these agents, KB001, is an anti-PcrV monoclonal antibody currently in clinical studies (19,20).…”

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confidence: 99%

Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System

Bowlin

Williams

Knoten

et al. 2014

Antimicrob Agents Chemother

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The type III secretion system (T3SS) is a clinically important virulence mechanism in Pseudomonas aeruginosa that secretes and translocates effector toxins into host cells, impeding the host's rapid innate immune response to infection. Inhibitors of T3SS may be useful as prophylactic or adjunctive therapeutic agents to augment the activity of antibiotics in P. aeruginosa infections, such as pneumonia and bacteremia. One such inhibitor, the phenoxyacetamide MBX 1641, exhibits very responsive structureactivity relationships, including striking stereoselectivity, in its inhibition of P. aeruginosa T3SS. These features suggest interaction with a specific, but unknown, protein target. Here, we identify the apparent molecular target by isolating inhibitor-resistant mutants and mapping the mutation sites by deep sequencing. Selection and sequencing of four independent mutants resistant to the phenoxyacetamide inhibitor MBX 2359 identified the T3SS gene pscF, encoding the needle apparatus, as the only locus of mutations common to all four strains. Transfer of the wild-type and mutated alleles of pscF, together with its chaperone and cochaperone genes pscE and pscG, to a ⌬pscF P. aeruginosa strain demonstrated that each of the single-codon mutations in pscF is necessary and sufficient to provide secretion and translocation that is resistant to a variety of phenoxyacetamide inhibitor analogs but not to T3SS inhibitors with different chemical scaffolds. These results implicate the PscF needle protein as an apparent new molecular target for T3SS inhibitor discovery and suggest that three other chemically distinct T3SS inhibitors interact with one or more different targets or a different region of PscF.

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confidence: 99%

Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System

Bowlin

Williams

Knoten

et al. 2014

Antimicrob Agents Chemother

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“…Mutants lacking a functional T3SS are severely attenuated for virulence in animal infection models (20,21,23,37), and a role for the T3SS has been implicated in human disease severity and progression (35). Several studies have examined therapeutic interventions targeting the T3SS, including inhibition of translocase activity (37), effector activity (25), and T3SS gene transcription (15). The latter approach involved isolation of small-molecule inhibitors of ExsA, the primary transcriptional regulator of T3SS gene expression.…”

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confidence: 99%

Orientation of Pseudomonas aeruginosa ExsA Monomers Bound to Promoter DNA and Base-Specific Contacts with the PexoT Promoter

King

Brutinel

Marsden

et al. 2012

Journal of Bacteriology

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“…T3SS proteins are attractive targets for 'anti-virulence' compounds because they are often essential to the virulence of widely distributed Gram-negative bacterial pathogens of plants, animals and humans. Recently, whole-cell-based high-throughput screens have been performed to identify T3SS inhibitors and have identified several classes of small-molecule compounds (salicylidene acylhydrazides, salicylanilides, sulfonylaminobenzanilides, benzimidazoles and a thiazolidinone) and three natural products as effective agents against a number of pathogenic bacteria that utilize the T3SS, including Yersinia, Chlamydia, Salmonella, enteropathogenic Escherichia coli and Shigella (Kauppi et al, 2003;Pan et al, 2007;Grier et al, 2010;Garrity-Ryan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis

Zigangirova

Kost

Didenko

et al. 2016

Journal of Medical Microbiology

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A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis Chlamydia trachomatis is one of the most common sexually transmitted pathogens in the world and often causes chronic inflammatory diseases that are insensitive to antibiotics. The type 3 secretion system (T3SS) of pathogenic bacteria is a promising target for therapeutic intervention aimed at bacterial virulence and can be an attractive alternative for the treatment of chronic infections. Recently, we have shown that a small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones produced through the chemical modification of the thiohydrazides of oxamic acids, designated CL-55, inhibited the intracellular growth of C. trachomatis in a T3SS-dependent manner. To assess the feasibility of CL-55 as a therapeutic agent, our aim was to determine which point(s) in the developmental cycle CL-55 affects. We found that CL-55 had no effect on the adhesion of elementary bodies (EBs) to host cells but significantly suppressed EB internalization. We further found that CL-55 inhibited the intracellular division of reticulate bodies (RBs). An ultrastructural analysis revealed loss of contact between the RBs and the inclusion membrane in the presence of CL-55. Finally, we found that our T3SS inhibitor prevented the persistence of Chlamydia in cell culture and its reversion to the infectious state. Our findings indicate that our T3SS inhibitor may be effective in the treatment of both productive and persistent infections.

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N-Hydroxybenzimidazole inhibitors of ExsA MAR transcription factor in Pseudomonas aeruginosa: In vitro anti-virulence activity and metabolic stability

Cited by 34 publications

References 12 publications

Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System

Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System

Orientation of Pseudomonas aeruginosa ExsA Monomers Bound to Promoter DNA and Base-Specific Contacts with the PexoT Promoter

A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis

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