QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens

Curtis, Meredith M.; Russell, Regan M.; Moreira, Cristiano G.; Adebesin, Adeniyi Michael; Wang, Chang-Guang; Williams, Noelle S.; Taussig, Ronald; Stewart, Don; Zimmern, Philippe E.; Lu, Biao; Prasad, Ravi N.; Zhu, Chen; Rasko, David A.; Huntley, Jason F.; Falck, John R.; Sperandio, Vanessa

doi:10.1128/mbio.02165-14

Cited by 121 publications

(122 citation statements)

References 33 publications

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“…Based on (i) our observation that QseC functions in AIEC persistence and exacerbated colitis in ex-ASF mice and (ii) work demonstrating that the QseC inhibitor LED209 reduces Enterobacteriaceae pathogen virulence in vivo (21,22), we examined the effects of QseC blockade on host disease status in three experimental colitis models maintained under SPF conditions. This approach would allow us to explore the translational applicability of a QseC-targeted antivirulence strategy for IBD.…”

Section: Resultsmentioning

confidence: 99%

“…a histidine sensor kinase activated on detection of microbiotagenerated autoinducer-3 (AI-3) or host stress signals, specifically the catecholamines (CAs) norepinephrine (NE) and epinephrine (EPI) (20). Both NE and EPI induce QseC-mediated virulence in vitro and blocking QseBC signaling with the QseC inhibitor LED209 reduces the in vivo virulence of Gram-negative pathogens, including enterohemorrhagic E. coli and Salmonella enterica Typhimurium (21)(22)(23)(24)(25). Previous surveys of stool from the T-bet −/− Rag2 −/− preclinical colitis model following various treatment interventions revealed microbial features that discriminate between active disease and remission.…”

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confidence: 99%

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QseC inhibition as an antivirulence approach for colitis-associated bacteria

Rooks

Veiga

Reeves

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet −/− Rag2 −/− IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.colitis | Escherichia coli | QseC | antivirulence | gut microbiome

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Rooks

Veiga

Reeves

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The sensor kinase QseC in Escherichia coli, Salmonella typhimurium, and F. tularensis is a known protein target/receptor of the small molecule LED209. 10,11 In F. tularensis SchuS4, QseC (FTT_0094c) was found to be a virulence factor and to be a target of LED209, a compound that can rescue mice from tularemia infection. 10,12 This molecule serves as an example of a TCS-targeting small-molecule that could be useful for further development as a new therapeutic; however, LED209 is not FDA approved.…”

Section: Introductionmentioning

confidence: 99%

Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida

Dean

Hoek

2015

Virulence

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Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDAapproved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.

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“…Another approach has been to find nontraditional therapeutics that target 2CSTS and do not cause cell death but downregulate the expression of virulence factors (13,16,17). For example, inhibition of the 2CSTS QseBC by the small molecule LED209 increased survival in animals infected with Salmonella enterica serovar Typhimurium or Francisella tularensis (18,19). Thus, there is a rationale to expand the repertoire of nontraditional therapeutics that target 2CSTS.…”

mentioning

confidence: 99%

Development and Validation of a High-Throughput Cell-Based Screen To Identify Activators of a Bacterial Two-Component Signal Transduction System

Rensburg

Fortney

Chen

et al. 2015

Antimicrob Agents Chemother

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iCpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in Salmonella enterica serovar Typhimurium and Haemophilus ducreyi are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of Escherichia coli strains containing a CpxR-P-responsive lacZ reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems. The increasing prevalence of multidrug-resistant Gram-negative bacteria has prompted urgent calls for new antibiotics (1). Escherichia coli sequence type 131, a clonal group that expresses extended-spectrum ␤-lactamases (ESBLs) and quinolone resistance, has emerged as a major cause of community-and health care-associated urinary tract infections in the United States (2-4). The Klebsiella pneumoniae carbapenemase (KPC) has rendered some strains of K. pneumoniae resistant to all ␤-lactams, while the New Delhi metallo-(NDM-1) ␤-lactamase-containing plasmid has rendered some strains of E. coli and K. pneumoniae panresistant (5-9). These developments raise the specter that several common infections, such as urinary tract infections due to E. coli or K. pneumoniae, may soon be caused by organisms that are virtually untreatable (5,8,9).The traditional approach to discover antibiotics has been to screen libraries of natural or synthetic products for bacterial killing activity in culture. Unfortunately, this strategy has yielded no new targets or classes of drugs for Gram-negative bacteria over the past 50 years (10-12). More contemporary approaches are aimed at identifying inhibitors of novel targets essential for growth or virulence. Attractive targets include bacterial two-component signal transduction systems (2CSTS), which ty...

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QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens

Cited by 121 publications

References 33 publications

QseC inhibition as an antivirulence approach for colitis-associated bacteria

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida

Development and Validation of a High-Throughput Cell-Based Screen To Identify Activators of a Bacterial Two-Component Signal Transduction System

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