Phylogenetic Classification of Diverse LysR-Type Transcriptional Regulators of a Model Prokaryote Geobacter sulfurreducens

Krushkal, Julia; Qu, Yanhua; Lovley, Derek R.; Adkins, Ronald M.

doi:10.1007/s00239-012-9498-z

Cited by 5 publications

(4 citation statements)

References 62 publications

(109 reference statements)

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“…M64, a 2 nd generation inhibitor identified by SAR, is the first identified compound that exhibits significant in vivo therapeutic efficacy against both acute and persistent mammalian infections. Furthermore, that LTTRs regulate virulence regulons in divergent bacterial pathogens [69], and QS functions throughout the eubacteria and archaebacteria, suggest that M64-based anti-infectives could have broad clinical potential against a wide-range of bacterial pathogens.…”

Section: Discussionmentioning

confidence: 99%

Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Starkey

Lépine

Maura³

et al. 2014

PLoS Pathog

241

306

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Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections.

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Section: Discussionmentioning

confidence: 99%

Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Starkey

Lépine

Maura³

et al. 2014

PLoS Pathog

241

306

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“…It has been proposed that the precursor LTTR arose early in the evolution of prokaryotes, based primarily on the significant genetic distances, distinct %GC profiles, and the diverse structures of the coinducers needed to activate or repress transcription (Schell, 1993). Schlaman et al (1992) reported three putative LTTR subgroups (n = 43) with no apparent common functions (i.e., different target genes, coinducers, and origin) among the LTTRs (Schlaman et al, 1992) Delta-proteobacteria revealed five distinct genetic lineages from the eight Geobacter sulfurreducens LTTR protein sequences within the Geobacteraceae (Krushkal et al, 2012). However, reports at the genus and species level are lacking and therefore we selected Pseudomonads, and in particular the nosocomial pathogen P. aeruginosa as a model organism for analysis and characterisation.…”

Section: Prevalence Of Lysr Among the Pseudomonadaceaementioning

confidence: 99%

“…The classical mechanism of LTTR action is regulation of a divergently transcribed promoter in response to activation by co-inducing signal. However, recent reports have highlighted the regulation of distantly transcribed promoters and promoters arranged as part of operon units with the respective LTTR (Krushkal et al, 2012;Maddocks and Oyston, 2008;Tian et al, 2009a). Therefore, the topology of LTTRs in P. aeruginosa was investigated using the PA14 strain as baseline.…”

Section: Distribution and Topology Of Lttr Proteins In P Aeruginosamentioning

confidence: 99%

“…By far the largest class of transcriptional regulator is the LysR-class, which is universal among both Gram-negative and Gram-positive bacteria. Since LysR-type Transcriptional Regulators (LTTRs) were first classified as a distinct regulatory family (Henikoff et al, 1988), the number of LTTRs identified has grown from 9 to over 40,000 (Krushkal et al, 2012;Maddocks and Oyston, 2008;Monferrer et al, 2010;Schell, 1993). Capable of mediating both signal dependent and signal-independent transcriptional regulation, LTTR orthologues are also found in archaea and eukaryotic organisms (Maddocks and Oyston, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Molecular evolution of LysR-type transcriptional regulation in Pseudomonas aeruginosa

Reen¹,

Barret²,

Fargier³

et al. 2013

Molecular Phylogenetics and Evolution

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Signal perception and transduction through tightly coordinated circuits is integral to the survival and persistence of microbes in diverse ecological niches. The capacity to adapt to changes in the environment is central to their ability to thrive under adverse circumstances. Signal dependent transcriptional regulators are a key mechanism through which microbes assimilate environmental cues and mediate the appropriate adaptive response. By far the largest class of transcriptional regulator is the LysR-class, which is universally distributed among bacteria, archaea, and even eukaryotic organisms. The number of LysR-Type Transcriptional Regulators (LTTRs) varies among species with one of the largest repertoires encoded in the genome of the nosocomial pathogen Pseudomonas aeruginosa. To understand the evolutionary basis for this, we undertook to analyse the relationship between the LTTRs, both at the species and genus level. Phylogenetic analysis of the complete Pseudomonas LTTR dataset revealed significant cluster patterns based on full length and domain analysis. Interestingly, evidence of acquisition through horizontal gene transfer was rare, with divergent evolution apparently favoured. Furthermore, genes that appear to have been acquired, as well as those with a non-classical topological arrangement were clustered in distinct groups in the phylogenetic trees, indicating some ancestral association. The conservation within clusters identified in this study will provide a useful platform for future molecular analyses.

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Identification of two combined genes responsible for dechlorination of 3,5,6-trichloro-2-pyridinol (TCP) in Cupriavidus pauculus P2

Cao

et al. 2013

Journal of Hazardous Materials

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Phylogenetic Classification of Diverse LysR-Type Transcriptional Regulators of a Model Prokaryote Geobacter sulfurreducens

Cited by 5 publications

References 62 publications

Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Molecular evolution of LysR-type transcriptional regulation in Pseudomonas aeruginosa

Identification of two combined genes responsible for dechlorination of 3,5,6-trichloro-2-pyridinol (TCP) in Cupriavidus pauculus P2

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