The agr Locus Regulates Virulence and Colonization Genes in Clostridium difficile 027

Abstract

The transcriptional regulator AgrA, a member of the LytTR family of proteins, plays a key role in controlling gene expression in some Gram-positive pathogens, including Staphylococcus aureus and Enterococcus faecalis. AgrA is encoded by the agrACDB global regulatory locus, and orthologues are found within the genome of most Clostridium difficile isolates, including the epidemic lineage 027/BI/NAP1. Comparative RNA sequencing of the wild type and otherwise isogenic agrA null mutant derivatives of C. difficile R20291 revealed a network of approximately 75 differentially regulated transcripts at late exponential growth phase, including many genes associated with flagellar assembly and function, such as the major structural subunit, FliC. Other differentially regulated genes include several involved in bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) synthesis and toxin A expression. C. difficile 027 R20291 agrA mutant derivatives were poorly flagellated and exhibited reduced levels of colonization and relapses in the murine infection model. Thus, the agr locus likely plays a contributory role in the fitness and virulence potential of C. difficile strains in the 027/BI/NAP1 lineage.

Potential Emergence of Multi-quorum Sensing Inhibitor Resistant (MQSIR) Bacteria

“…Clostridium are noted to contain either single or multiple QSS, such as: (1) LuxS, (2) Agr, (3) Agr2 that are regulated by peptide signals e.g., AIP ( Table 1) [24][25][26][27][28][29]. Table 1) [30][31][32][33][34].…”

Gene Regulation, Two Component Regulatory Systems, and Adaptive Responses in Treponema Denticola

“…The validity of the AtcR regulon defined here is supported by studies of the AgrA regulon of C. difficile (Martin et al 2013). There is considerable overlap in the functional classification of genes regulated by AgrA and AtcR, most notably between those that encode proteins involved in flagellar assembly, structure, and function.…”

“…Although LytTR domains are widespread among human and plant bacterial pathogens, they are present in only a small subset of RRs (typically 1 or 2 per bacterial genome) (Galperin 2008). LytTR RRs contribute to the regulation of diverse processes and activities, including biofilm formation (Lizewski et al 2004), toxin production (Ba-Thein et al 1996;Lyristis et al 1994), type IV pili synthesis (Belete et al 2008), antimicrobial peptide production (Risoen et al 1998), flagellar assembly, flagellar function (Martin et al 2013), natural competence (Streptococcus pneumoniae) (de Saizieu et al 2000), extracellular polysaccharide biosynthesis (Pseudomonas aeruginosa) (Lizewski et al 2004;Morici et al 2007), overall fitness and virulence gene expression (Abdelnour et al 1993;Martin et al 2013). It is noteworthy that among the Spirochaetaceae, only T. denticola, T. bryantii (identifier WP_022932649) and Sphaerochaeta globosa (WP_013608153) encode LytTR domain-containing proteins (Frederick et al 2008.…”

“…There is considerable overlap in the functional classification of genes regulated by AgrA and AtcR, most notably between those that encode proteins involved in flagellar assembly, structure, and function. In C. difficile, AgrA is a transcriptional activator of flagellar synthesis (Martin et al 2013). Overlap was also observed for genes involved in metabolism and transport.…”

“…Using recombinant proteins and in vitro autophosphorylation and phosphotransfer assays, it was TDE2225 acyl-CoA thioesterase For operons, the promoter designation is shown only for the first gene in the operon. Genes that are part of the LytTR regulon of C. difficile (Martin et al 2013) are indicated by an asterisk. This updated table is derived information presented in an earlier study (Miller et al 2014a) demonstrated that Hpk2 and Rrp2 constitute a functional TCR (Sarkar et al 2010).…”