Small Molecule Inhibitors of LcrF, a
            <i>Yersinia pseudotuberculosis</i>
            Transcription Factor, Attenuate Virulence and Limit Infection in a Murine Pneumonia Model

Garrity-Ryan, Lynne; Kim, Oak K.; Balada-Llasat, Joan-Miquel; Bartlett, Victoria J.; Verma, Atul Kumar; Fisher, Michael L.; Castillo, Cynthia; Songsungthong, Warangkhana; Tanaka, Sébastien; Levy, Stuart B.; Mecsas, Joan; Alekshun, Michael N.

doi:10.1128/iai.01305-09

Cited by 69 publications

(61 citation statements)

References 44 publications

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“…Indeed, a number of chemical inhibitors of TCSs have been identified by screening libraries of synthetic compounds (74,83). Furthermore, small chemical molecules targeting different virulence factors have been shown to be useful in preventing infection from different pathogens (13,14,27,59). In this manner, small molecules targeting the Pst system or PhoBR could be considered as therapeutic agents to constitutively activate the Pho regulon and potentially prevent such pathogens from causing infections.…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of Type 1 Fimbriae by apstMutant of Uropathogenic Escherichia coli Reduces Urinary Tract Infection

et al. 2012

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The pstSCAB-phoU operon encodes the phosphate-specific transport system (Pst). Loss of Pst constitutively activates the Pho regulon and decreases bacterial virulence. However, specific mechanisms underlying decreased bacterial virulence through inactivation of Pst are poorly understood. In uropathogenic Escherichia coli (UPEC) strain CFT073, inactivation of pst decreased urinary tract colonization in CBA/J mice. The pst mutant was deficient in production of type 1 fimbriae and showed decreased expression of the fimA structural gene which correlated with differential expression of the fimB, fimE, ipuA, and ipbA genes, encoding recombinases, mediating inversion of the fim promoter. The role of fim downregulation in attenuation of the pst mutant was confirmed using a fim phase-locked-on derivative, which demonstrated a significant gain in virulence. In addition, the pst mutant was less able to invade human bladder epithelial cells. Since type 1 fimbriae contribute to UPEC virulence by promoting colonization and invasion of bladder cells, the reduced bladder colonization by the pst mutant is predominantly attributed to downregulation of these fimbriae. Elucidation of mechanisms mediating the control of type 1 fimbriae through activation of the Pho regulon in UPEC may open new avenues for therapeutics or prophylactics against urinary tract infections. Pathogenic Escherichia coli comprises a diversity of strains associated with both intestinal and extraintestinal infections (39). Urinary tract infections (UTIs) are one of the most common bacterial infections, and uropathogenic E. coli (UPEC) is the predominant causal agent, representing up to 85% of communityacquired UTIs (28). In addition to causing UTIs, extraintestinal pathogenic E. coli (ExPEC) is an important pathogen associated with neonatal meningitis and septicemia in humans, as well as systemic infections in poultry and livestock (60, 61). Many virulence factors associated with UPEC strains are important for establishing infection, and these include adhesins, toxins, iron acquisition systems, and capsular antigens (53).An important aspect of bacterial virulence is the capacity to rapidly adapt to changes and stresses encountered during infection of the host, since changes in the host environment may serve as cues mediating regulation of expression of key virulence factors during infection (25,47). One of the mechanisms by which bacteria respond to environmental signals is through two-component signal transduction systems (TCSs). TCSs are composed of an inner-membrane histidine kinase sensor protein and cytoplasmic response regulator (81). TCSs are important for bacterial adaptation and virulence (6, 12), and a number of TCSs have been identified to be important for pathogenic E. coli, e.g., BarA-UvrY, PhoPQ, and QseBC (4, 31, 41, 56).The Pho regulon is controlled by the PhoBR TCS, in which PhoR is the sensor histidine kinase and PhoB the response regulator. PhoBR responds to phosphate limitation, i.e., when the extracellular phosphate concentration falls belo...

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Section: Discussionmentioning

confidence: 99%

Decreased Expression of Type 1 Fimbriae by apstMutant of Uropathogenic Escherichia coli Reduces Urinary Tract Infection

et al. 2012

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“…Other studies concluded that the inhibitor affects the actual number of T3S systems and flagella assembled in Salmonella (6). Additional studies to identify inhibitors were targeted against specific proteins of the Yersinia T3S system; YopH (7), LcrF (8), and YscN (9) have all been successful targets of such studies. The ability of these compounds to be effective in species other than Yersinia has yet to be established.…”

mentioning

confidence: 99%

A Type III Secretion System Inhibitor Targets YopD while Revealing Differential Regulation of Secretion in Calcium-Blind Mutants of Yersinia pestis

Jessen

Bradley

Nilles

2014

Antimicrob Agents Chemother

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“…The Nhydroxybenzimidazoles inhibit the DNA-binding activity of AraC family proteins, including ExsA (32,33,42). The IC 50 s for the N-hydroxybenzimidazole inhibitors used in this study ranged from 8 to 45 M for ExsA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by N -Hydroxybenzimidazoles

Marsden

King

Spies

et al. 2016

Antimicrob Agents Chemother

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Small Molecule Inhibitors of LcrF, a Yersinia pseudotuberculosis Transcription Factor, Attenuate Virulence and Limit Infection in a Murine Pneumonia Model

Cited by 69 publications

References 44 publications

Decreased Expression of Type 1 Fimbriae by apstMutant of Uropathogenic Escherichia coli Reduces Urinary Tract Infection

Decreased Expression of Type 1 Fimbriae by apstMutant of Uropathogenic Escherichia coli Reduces Urinary Tract Infection

A Type III Secretion System Inhibitor Targets YopD while Revealing Differential Regulation of Secretion in Calcium-Blind Mutants of Yersinia pestis

Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by N -Hydroxybenzimidazoles

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