Burkholderia pseudomallei as an Enteric Pathogen: Identification of Virulence Factors Mediating Gastrointestinal Infection

ABSTRACTBurkholderia pseudomallei is a Gram-negative bacterium and the causative agent of melioidosis. Despite advances in our understanding of the disease, B. pseudomallei poses a significant health risk, especially in regions of endemicity, where treatment requires prolonged antibiotic therapy. Even though the respiratory and percutaneous routes are well documented and considered the main ways to acquire the pathogen, the gastrointestinal tract is believed to be an underreported and underrecognized route of infection. In the present study, we describe the development of in vitro and in vivo models to study B. pseudomallei gastrointestinal infection. Further, we report that the type 6 secretion system (T6SS) and type 1 fimbriae are important virulence factors required for gastrointestinal infection. Using a human intestinal epithelial cell line and mouse primary intestinal epithelial cells (IECs), we demonstrated that B. pseudomallei adheres, invades, and forms multinucleated giant cells, ultimately leading to cell toxicity. We demonstrated that mannose-sensitive type 1 fimbria is involved in the initial adherence of B. pseudomallei to IECs, although the impact on full virulence was limited. Finally, we also showed that B. pseudomallei requires a functional T6SS for full virulence, bacterial dissemination, and lethality in mice infected by the intragastric route. Overall, we showed that B. pseudomallei is an enteric pathogen and that type 1 fimbria is important for B. pseudomallei intestinal adherence, and we identify a new role for T6SS as a key virulence factor in gastrointestinal infection. These studies highlight the importance of gastrointestinal melioidosis as an understudied route of infection and open a new avenue for the pathogenesis of B. pseudomallei.

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Whole-genome comparative analysis of Malaysian Burkholderia pseudomallei clinical isolates

Microbial Genomics ◽

10.1099/mgen.0.000527 ◽

2021 ◽

Vol 7 (2) ◽

Author(s):

Ahmad-Kamal Ghazali ◽

Su-Anne Eng ◽

Jia-Shiun Khoo ◽

Seddon Teoh ◽

Chee-Choong Hoh ◽

...

Keyword(s):

Comparative Analysis ◽

Virulence Factors ◽

Type Species ◽

Burkholderia Pseudomallei ◽

Clinical Manifestations ◽

Phylogenomic Analysis ◽

Content Type ◽

Link Type ◽

Multiple Organs ◽

The Difference

Burkholderia pseudomallei , a soil-dwelling Gram-negative bacterium, is the causative agent of the endemic tropical disease melioidosis. Clinical manifestations of B. pseudomallei infection range from acute or chronic localized infection in a single organ to fulminant septicaemia in multiple organs. The diverse clinical manifestations are attributed to various factors, including the genome plasticity across B. pseudomallei strains. We previously characterized B. pseudomallei strains isolated in Malaysia and noted different levels of virulence in model hosts. We hypothesized that the difference in virulence might be a result of variance at the genome level. In this study, we sequenced and assembled four Malaysian clinical B. pseudomallei isolates, UKMR15, UKMPMC2000, UKMD286 and UKMH10. Phylogenomic analysis showed that Malaysian subclades emerged from the Asian subclade, suggesting that the Malaysian strains originated from the Asian region. Interestingly, the low-virulence strain, UKMH10, was the most distantly related compared to the other Malaysian isolates. Genomic island (GI) prediction analysis identified a new island of 23 kb, GI9c, which is present in B. pseudomallei and Burkholderia mallei , but not Burkholderia thailandensis . Genes encoding known B. pseudomallei virulence factors were present across all four genomes, but comparative analysis of the total gene content across the Malaysian strains identified 104 genes that are absent in UKMH10. We propose that these genes may encode novel virulence factors, which may explain the reduced virulence of this strain. Further investigation on the identity and role of these 104 proteins may aid in understanding B. pseudomallei pathogenicity to guide the design of new therapeutics for treating melioidosis.

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Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00235-13 ◽

2013 ◽

Vol 57 (6) ◽

pp. 2694-2704 ◽

Cited By ~ 61

Author(s):

Mai Alhajlan ◽

Moayad Alhariri ◽

Abdelwahab Omri

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Virulence Factors ◽

Biological Fluid ◽

Free Drug ◽

Clinical Isolates ◽

Epithelial Cell Line ◽

Efficacy And Safety ◽

Surface Charges ◽

Content Type

ABSTRACTWe investigated the efficacy and safety of liposomal clarithromycin formulations with different surface charges against clinical isolates ofPseudomonas aeruginosafrom the lungs of cystic fibrosis (CF) patients. The liposomal clarithromycin formulations were prepared by the dehydration-rehydration method, and their sizes were measured using the dynamic-light-scattering technique. Encapsulation efficiency was determined by microbiological assay, and the stabilities of the formulations in biological fluid were evaluated for a period of 48 h. The MICs and minimum bactericidal concentrations (MBCs) of free and liposomal formulations were determined withP. aeruginosastrains isolated from CF patients. Liposomal clarithromycin activity against biofilm-formingP. aeruginosawas compared to that of free antibiotic using the Calgary Biofilm Device (CBD). The effects of subinhibitory concentrations of free and liposomal clarithromycin on bacterial virulence factors and motility on agar were investigated on clinical isolates ofP. aeruginosa. The cytotoxicities of the liposome preparations and free drug were evaluated on a pulmonary epithelial cell line (A549). The average diameter of the formulations was >222 nm, with encapsulation efficiencies ranging from 5.7% to 30.4%. The liposomes retained more than 70% of their drug content during the 48-h time period. The highly resistant strains ofP. aeruginosabecame susceptible to liposome-encapsulated clarithromycin (MIC, 256 mg/liter versus 8 mg/liter;P< 0.001). Liposomal clarithromycin reduced the bacterial growth within the biofilm by 3 to 4 log units (P< 0.001), significantly attenuated virulence factor production, and reduced bacterial twitching, swarming, and swimming motilities. The clarithromycin-entrapped liposomes were less cytotoxic than the free drug (P< 0.001). These data indicate that our novel formulations could be a useful strategy to enhance the efficacy of clarithromycin against resistantP. aeruginosastrains that commonly affect individuals with cystic fibrosis.

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Staphylococcus aureus Arsenal To Conquer the Lower Respiratory Tract

mSphere ◽

10.1128/msphere.00059-21 ◽

2021 ◽

Vol 6 (3) ◽

Author(s):

Mariane Pivard ◽

Karen Moreau ◽

François Vandenesch

Keyword(s):

Staphylococcus Aureus ◽

Respiratory Tract ◽

Virulence Factors ◽

Lower Respiratory Tract ◽

Defense Mechanisms ◽

Future Research ◽

Epithelial Barrier ◽

Content Type ◽

Wide Range ◽

The Impact

ABSTRACT Staphylococcus aureus is both a commensal and a pathogenic bacterium for humans. Its ability to induce severe infections is based on a wide range of virulence factors. S. aureus community-acquired pneumonia (SA-CAP) is rare and severe, and the contribution of certain virulence factors in this disease has been recognized over the past 2 decades. First, the factors involved in metabolism adaptation are crucial for S. aureus survival in the lower respiratory tract, and toxins and enzymes are required for it to cross the pulmonary epithelial barrier. S. aureus subsequently faces host defense mechanisms, including the epithelial barrier, but most importantly the immune system. Here, again, S. aureus uses myriad virulence factors to successfully escape from the host’s defenses and takes advantage of them. The impact of S. aureus virulence, combined with the collateral damage caused by an overwhelming immune response, leads to severe tissue damage and adverse clinical outcomes. In this review, we summarize step by step all of the S. aureus factors implicated in CAP and described to date, and we provide an outlook for future research.

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Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease

mBio ◽

10.1128/mbio.01298-15 ◽

2015 ◽

Vol 6 (6) ◽

Cited By ~ 29

Author(s):

Adeline Sivignon ◽

Xibo Yan ◽

Dimitri Alvarez Dorta ◽

Richard Bonnet ◽

Julie Bouckaert ◽

...

Keyword(s):

Escherichia Coli ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Intestinal Inflammation ◽

Intestinal Epithelial ◽

Content Type ◽

Type 1 Pili

ABSTRACTThe ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasiveEscherichia coli(AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives ofn-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were testedin vitroin IEC infected with the AIEC LF82 strain andin vivoby oral administration to CEACAM6-expressing mice infected with LF82 bacteria.In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacyin vivoin decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or β-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effectsin vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators.IMPORTANCECurrent treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasiveEscherichia coli(AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cellsin vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observedin vivoin AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.

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Glucosylation of Rho GTPases by Clostridium difficile toxin A triggers apoptosis in intestinal epithelial cells

Journal of Medical Microbiology ◽

10.1099/jmm.0.47769-0 ◽

2008 ◽

Vol 57 (6) ◽

pp. 765-770 ◽

Cited By ~ 71

Author(s):

Ralf Gerhard ◽

Stefanie Nottrott ◽

Janett Schoentaube ◽

Helma Tatge ◽

Alexandra Olling ◽

...

Keyword(s):

Clostridium Difficile ◽

Actin Cytoskeleton ◽

Rho Gtpases ◽

Small Gtpases ◽

Epithelial Cell Line ◽

Intestinal Epithelial ◽

Single Chain ◽

Toxin A ◽

Induced Apoptosis ◽

The Impact

The intestinal epithelial cell line HT-29 was used to study the apoptotic effect of Clostridium difficile toxin A (TcdA). TcdA is a 300 kDa single-chain protein, which glucosylates and thereby inactivates small GTPases of the Rho family (Rho, Rac and Cdc42). The effect of TcdA-catalysed glucosylation of the Rho GTPases is well known: reorganization of the actin cytoskeleton with accompanying morphological changes in cells, leading to complete rounding of cells and destruction of the intestinal barrier function. Less is known about the mechanism by which apoptosis is induced in TcdA-treated cells. In this study, TcdA induced the activation of caspase-3, -8 and -9. Apoptosis, as estimated by the DNA content of cells, started as early as 24 h after the addition of TcdA. The impact of Rho glucosylation was obvious when mutant TcdA with reduced or deficient glucosyltransferase activity was applied. TcdA mutant W101A, with 50-fold reduced glucosyltransferase activity, induced apoptosis only at an equipotent concentration compared with wild-type TcdA at a 50 % effective concentration of 0.2 nM. The enzyme-deficient mutant TcdA D285/287N was not able to induce apoptosis. Apoptosis induced by TcdA strictly depended on the activation of caspases, and was completely blocked by the pan-caspase inhibitor z-VAD-fmk. Destruction of the actin cytoskeleton by latrunculin B was not sufficient to induce apoptosis, indicating that apoptosis induced by TcdA must be due to another mechanism. In summary, TcdA-induced apoptosis (cytotoxic effect) depends on the glucosylation of Rho GTPases, but is not triggered by destruction of the actin cytoskeleton (cytopathic effect).

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CRISPR Screen Reveals that EHEC’s T3SS and Shiga Toxin Rely on Shared Host Factors for Infection

mBio ◽

10.1128/mbio.01003-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 21

Author(s):

Alline R. Pacheco ◽

Jacob E. Lazarus ◽

Brandon Sit ◽

Stefanie Schmieder ◽

Wayne I. Lencer ◽

...

Keyword(s):

Virulence Factors ◽

Type Iii Secretion ◽

Diarrheal Disease ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Content Type ◽

Shiga Toxins ◽

Genome Wide ◽

A Genome ◽

Sphingolipid Biosynthesis

ABSTRACTEnterohemorrhagicEscherichia coli(EHEC) has two critical virulence factors—a type III secretion system (T3SS) and Shiga toxins (Stxs)—that are required for the pathogen to colonize the intestine and cause diarrheal disease. Here, we carried out a genome-wide CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats with Cas9) loss-of-function screen to identify host loci that facilitate EHEC infection of intestinal epithelial cells. Many of the guide RNAs identified targeted loci known to be associated with sphingolipid biosynthesis, particularly for production of globotriaosylceramide (Gb3), the Stx receptor. Two loci (TM9SF2 and LAPTM4A) with largely unknown functions were also targeted. Mutations in these loci not only rescued cells from Stx-mediated cell death, but also prevented cytotoxicity associated with the EHEC T3SS. These mutations interfered with early events associated with T3SS and Stx pathogenicity, markedly reducing entry of T3SS effectors into host cells and binding of Stx. The convergence of Stx and T3SS onto overlapping host targets provides guidance for design of new host-directed therapeutic agents to counter EHEC infection.IMPORTANCEEnterohemorrhagicEscherichia coli(EHEC) has two critical virulence factors—a type III secretion system (T3SS) and Shiga toxins (Stxs)—that are required for colonizing the intestine and causing diarrheal disease. We screened a genome-wide collection of CRISPR mutants derived from intestinal epithelial cells and identified mutants with enhanced survival following EHEC infection. Many had mutations that disrupted synthesis of a subset of lipids (sphingolipids) that includes the Stx receptor globotriaosylceramide (Gb3) and hence protect against Stx intoxication. Unexpectedly, we found that sphingolipids also mediate early events associated with T3SS pathogenicity. Since antibiotics are contraindicated for the treatment of EHEC, therapeutics targeting sphingolipid biosynthesis are a promising alternative, as they could provide protection against both of the pathogen’s key virulence factors.

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Mapping the Global Network of Extracellular Protease Regulation in Staphylococcus aureus

mSphere ◽

10.1128/msphere.00676-19 ◽

2019 ◽

Vol 4 (5) ◽

Cited By ~ 6

Author(s):

Brittney D. Gimza ◽

Maria I. Larias ◽

Bridget G. Budny ◽

Lindsey N. Shaw

Keyword(s):

Staphylococcus Aureus ◽

Virulence Factors ◽

Global Network ◽

Protease Production ◽

Pathogenic Potential ◽

Content Type ◽

Regulatory Circuit ◽

Primary Network ◽

The Impact ◽

Protease Expression

ABSTRACT A primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring the regulation of the four protease loci by known and novel factors. In so doing, we determined that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, while the spl operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring scpA expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of S. aureus, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily, these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appears to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to S. aureus physiology and pathogenic potential. IMPORTANCE The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus.

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Role for FimH in Extraintestinal Pathogenic Escherichia coli Invasion and Translocation through the Intestinal Epithelium

Infection and Immunity ◽

10.1128/iai.00581-17 ◽

2017 ◽

Vol 85 (11) ◽

Cited By ~ 11

Author(s):

Nina M. Poole ◽

Sabrina I. Green ◽

Anubama Rajan ◽

Luz E. Vela ◽

Xi-Lei Zeng ◽

...

Keyword(s):

Escherichia Coli ◽

Virulence Factors ◽

Intestinal Epithelium ◽

Multidrug Resistant ◽

Ex Situ ◽

Healthy Population ◽

Gene Encoding ◽

Content Type ◽

Tract Infections

ABSTRACT The translocation of bacteria across the intestinal epithelium of immunocompromised patients can lead to bacteremia and life-threatening sepsis. Extraintestinal pathogenic Escherichia coli (ExPEC), so named because this pathotype infects tissues distal to the intestinal tract, is a frequent cause of such infections, is often multidrug resistant, and chronically colonizes a sizable portion of the healthy population. Although several virulence factors and their roles in pathogenesis are well described for ExPEC strains that cause urinary tract infections and meningitis, they have not been linked to translocation through intestinal barriers, a fundamentally distant yet important clinical phenomenon. Using untransformed ex situ human intestinal enteroids and transformed Caco-2 cells, we report that ExPEC strain CP9 binds to and invades the intestinal epithelium. ExPEC harboring a deletion of the gene encoding the mannose-binding type 1 pilus tip protein FimH demonstrated reduced binding and invasion compared to strains lacking known E. coli virulence factors. Furthermore, in a murine model of chemotherapy-induced translocation, ExPEC lacking fimH colonized at levels comparable to that of the wild type but demonstrated a statistically significant reduction in translocation to the kidneys, spleen, and lungs. Collectively, this study indicates that FimH is important for ExPEC translocation, suggesting that the type 1 pilus is a therapeutic target for the prevention of this process. Our study also highlights the use of human intestinal enteroids in the study of enteric diseases.

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The Increased Accumulation of Staphylococcus aureus Virulence Factors Is Maximized in a purR Mutant by the Increased Production of SarA and Decreased Production of Extracellular Proteases

Infection and Immunity ◽

10.1128/iai.00718-20 ◽

2021 ◽

Vol 89 (4) ◽

Author(s):

Duah Alkam ◽

Piroon Jenjaroenpun ◽

Aura M. Ramirez ◽

Karen E. Beenken ◽

Horace J. Spencer ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Virulence Factors ◽

Binding Proteins ◽

Protease Production ◽

Alpha Toxin ◽

Extracellular Proteases ◽

Content Type ◽

Enhanced Production ◽

Fibronectin Binding ◽

The Impact

ABSTRACT Mutation of purR was previously shown to enhance the virulence of Staphylococcus aureus in a murine sepsis model, and this cannot be fully explained by increased expression of genes within the purine biosynthesis pathway. Rather, the increased production of specific S. aureus virulence factors, including alpha toxin and the fibronectin-binding proteins, was shown to play an important role. Mutation of purR was also shown previously to result in increased abundance of SarA. Here, we demonstrate by transposon sequencing that mutation of purR in the USA300 strain LAC increases fitness in a biofilm while mutation of sarA has the opposite effect. Therefore, we assessed the impact of sarA on reported purR-associated phenotypes by characterizing isogenic purR, sarA, and sarA/purR mutants. The results confirmed that mutation of purR results in increased abundance of alpha toxin, protein A, the fibronectin-binding proteins, and SarA, decreased production of extracellular proteases, an increased capacity to form a biofilm, and increased virulence in an osteomyelitis model. Mutation of sarA had the opposite effects on all of these phenotypes and, other than bacterial burdens in the bone, all of the phenotypes of sarA/purR mutants were comparable to those of sarA mutants. Limiting the production of extracellular proteases reversed all of the phenotypes of sarA mutants and most of those of sarA/purR mutants. We conclude that a critical component defining the virulence of a purR mutant is the enhanced production of SarA, which limits protease production to an extent that promotes the accumulation of critical S. aureus virulence factors.

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Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic Escherichia coli

mBio ◽

10.1128/mbio.02038-14 ◽

2014 ◽

Vol 5 (6) ◽

Cited By ~ 42

Author(s):

Sarah E. Greene ◽

Jerome S. Pinkner ◽

Erik Chorell ◽

Karen W. Dodson ◽

Carrie L. Shaffer ◽

...

Keyword(s):

Escherichia Coli ◽

Virulence Factors ◽

Bacterial Infections ◽

Antibiotic Resistant ◽

Gram Negative ◽

Content Type ◽

Pilus Biogenesis ◽

Altered Regulation ◽

Tract Infections

ABSTRACTChaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of thefimSpromoter element, which can oscillate between phase on and phase off orientations. ec240 induced thefimSphase off orientation, and this effect was necessary for the majority of ec240’s inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce thefimSpromoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenicEscherichia coli(UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound.IMPORTANCECUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.

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