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Scott J. Hultgren - One of the best experts on this subject based on the ideXlab platform.

  • Uropathogenic Escherichia Coli Virulence and Gene Regulation
    Regulation of Bacterial Virulence, 2016
    Co-Authors: Drew J. Schwartz, Scott J. Hultgren
    Abstract:

    This chapter describes the virulence and regulation of chaperone-usher pathway (CUP) pili, focusing on type 1 and P pili in Uropathogenic Escherichia Coli (UPEC), the most common cause of urinary tract infections (UTIs). UPEC and E. Coli in general heavily rely on CUP pili to mediate attachment to biotic and abiotic surfaces. The pathogenesis of community-acquired UPEC UTI is thought to begin with UPEC colonization of the periurethral area from the fecal flora. Depending on the specific niche UPEC inhabits, it encounters different elements of the immune response as well as different environmental pressures, necessitating precise gene regulation. The ability of UPEC to transcend the acute population bottleneck is described in detail. In addition to up-regulation of genes involved in general metabolism, several genes classified as being involved in removal of reactive oxygen species and hydrophobic compounds were also upregulated. Further, negative cross-regulatory interactions between pili may serve to divert resources to the conditions most effective for persistence or transit throughout hosts. Antivirulence compounds such as pilicides and mannosides represent novel strategies to translate basic knowledge from the investigation of pilus structure and function into new therapeutics that may have efficacy in treating UTIs by affecting CUP expression and function.

  • Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in Uropathogenic Escherichia Coli
    Tetrahedron Letters, 2007
    Co-Authors: Nils Pemberton, Scott J. Hultgren, Jerome S. Pinkner, Jennifer M. Jones, Lotta Jakobsson, Fredrik Almqvist
    Abstract:

    Substituted bicyclic 2-pyridones, termed pilicides, prevent pilus assembly in Uropathogenic Escherichia Coli. Based on the bioactive methyl ester protected 2-pyridone 4, further functionalization at C-6 has yielded a set of new compounds, which have been evaluated for their ability to inhibit pilus formation in Uropathogenic E. Coli. The key intermediate in the synthesis was formylated 2-pyridone 5, which could be obtained via a Vilsmeier reaction. This versatile intermediate was converted into secondary and tertiary amines via reductive amination and could also be converted to other interesting functionalities using simple chemical transformations.

  • Intracellular bacterial communities of Uropathogenic Escherichia Coli in urinary tract pathogenesis
    Trends in microbiology, 2004
    Co-Authors: Gregory G. Anderson, Karen W. Dodson, Thomas M. Hooton, Scott J. Hultgren
    Abstract:

    Urinary tract infections in young, healthy women frequently recur, despite their traditional classification as acute infections. Conventional wisdom dictates that uropathogens causing recurrent infections in such individuals come from the fecal or vaginal flora, in the same manner as the initial infection. However, recent studies of Uropathogenic Escherichia Coli have found that it can carry out a complex developmental program within the superficial epithelial cells of the mouse bladder, forming intracellular bacterial communities with many biofilm-like properties. These intracellular biofilms allow the bacteria to outlast a strong host immune response to establish a dormant reservoir of pathogens inside the bladder cells. Re-emergence of bacteria from this reservoir might be the source of recurrent infection.

  • Recent advances into the pathogenesis of recurrent urinary tract infections: the bladder as a reservoir for Uropathogenic Escherichia Coli.
    International journal of antimicrobial agents, 2002
    Co-Authors: Joel D. Schilling, Scott J. Hultgren
    Abstract:

    Recurrent cystitis is a common clinical entity that is becoming increasingly challenging to manage. The current thought regarding the pathogenesis of these infections is evolving as new data emerges to suggest that some recurrences may originate from previously unrecognized reservoirs of Uropathogenic Escherichia Coli. This article will summarize recent conceptual changes with respect to the aetiology of recurrent urinary tract infections, particularly as it relates to chronic bacterial persistence in the bladder.

  • Design and evaluation of pilicides: potential novel antibacterial agents directed against Uropathogenic Escherichia Coli.
    Chembiochem : a European journal of chemical biology, 2001
    Co-Authors: Anette Svensson, Andreas Larsson, Hans Emtenäs, Mattias Hedenström, Tomas Fex, Scott J. Hultgren, Jerome S. Pinkner, Fredrik Almqvist, Jan Kihlberg
    Abstract:

    Design and evaluation of Pilicides : Potential novel antibacterial agents directed against Uropathogenic Escherichia Coli

Harry L. T. Mobley - One of the best experts on this subject based on the ideXlab platform.

  • rapid growth of Uropathogenic Escherichia Coli during human urinary tract infection
    Mbio, 2018
    Co-Authors: Valerie S Forsyth, Chelsie E Armbruster, Sara N Smith, Ali Pirani, Cody A Springman, Matthew S Walters, Greta R Nielubowicz, Stephanie D Himpsl, Evan S Snitkin, Harry L. T. Mobley
    Abstract:

    Uropathogenic Escherichia Coli (UPEC) strains cause most uncomplicated urinary tract infections (UTIs). These strains are a subgroup of extraintestinal pathogenic E. Coli (ExPEC) strains that infect extraintestinal sites, including urinary tract, meninges, bloodstream, lungs, and surgical sites. Here, we hypothesize that UPEC isolates adapt to and grow more rapidly within the urinary tract than other E. Coli isolates and survive in that niche. To date, there has not been a reliable method available to measure their growth rate in vivo Here we used two methods: segregation of nonreplicating plasmid pGTR902, and peak-to-trough ratio (PTR), a sequencing-based method that enumerates bacterial chromosomal replication forks present during cell division. In the murine model of UTI, UPEC strain growth was robust in vivo, matching or exceeding in vitro growth rates and only slowing after reaching high CFU counts at 24 and 30 h postinoculation (hpi). In contrast, asymptomatic bacteriuria (ABU) strains tended to maintain high growth rates in vivo at 6, 24, and 30 hpi, and population densities did not increase, suggesting that host responses or elimination limited population growth. Fecal strains displayed moderate growth rates at 6 hpi but did not survive to later times. By PTR, E. Coli in urine of human patients with UTIs displayed extraordinarily rapid growth during active infection, with a mean doubling time of 22.4 min. Thus, in addition to traditional virulence determinants, including adhesins, toxins, iron acquisition, and motility, very high growth rates in vivo and resistance to the innate immune response appear to be critical phenotypes of UPEC strains.IMPORTANCE Uropathogenic Escherichia Coli (UPEC) strains cause most urinary tract infections in otherwise healthy women. While we understand numerous virulence factors are utilized by E. Coli to colonize and persist within the urinary tract, these properties are inconsequential unless bacteria can divide rapidly and survive the host immune response. To determine the contribution of growth rate to successful colonization and persistence, we employed two methods: one involving the segregation of a nonreplicating plasmid in bacteria as they divide and the peak-to-trough ratio, a sequencing-based method that enumerates chromosomal replication forks present during cell division. We found that UPEC strains divide extraordinarily rapidly during human UTIs. These techniques will be broadly applicable to measure in vivo growth rates of other bacterial pathogens during host colonization.

  • Discovery of nicoyamycin A, an inhibitor of Uropathogenic Escherichia Coli growth in low iron environments
    Chemical communications (Cambridge England), 2017
    Co-Authors: Laura A. Mike, Ashootosh Tripathi, Connor M. Blankenship, Alyssa Saluk, Pamela J. Schultz, Giselle Tamayo-castillo, David H. Sherman, Harry L. T. Mobley
    Abstract:

    High-throughput screening and activity-guided purification identified nicoyamycin A, a natural product comprised of an uncommon 3-methyl-1,4-dioxane ring incorporated into a desferrioxamine-like backbone via a spiroaminal linkage. Nicoyamycin A potently inhibits Uropathogenic Escherichia Coli growth in low iron medium, a promising step toward developing novel antibiotics to treat recalcitrant bacterial infections.

  • Virulence and Fitness Determinants of Uropathogenic Escherichia Coli.
    Microbiology spectrum, 2015
    Co-Authors: Sargurunathan Subashchandrabose, Harry L. T. Mobley
    Abstract:

    Urinary tract infection (UTI) caused by Uropathogenic Escherichia Coli (UPEC) is a major global public health concern. Increasing antibiotic resistance found in clinical UPEC isolates underscores the immediate need for development of novel therapeutics against this pathogen. Better understanding of the fitness and virulence mechanisms that are integral to the pathogenesis of UTI will facilitate identification of novel strategies to prevent and treat infection with UPEC. Working towards that goal, the global UPEC research community has made great strides at unraveling various virulence and fitness genes. Here, we summarize major findings on virulence and fitness determinants that enable UPEC to successfully survive and colonize the urinary tract of mammalian hosts. Major sections of this chapter are devoted to the role of iron acquisition systems, metabolic pathways, fimbriae, flagella, toxins, biofilm formation, capsule, and strain-specific genes in the initiation and progression of UTIs. Transcriptomes of UPEC during experimental UTI in a murine model and naturally occurring UTI in women are compared to elucidate virulence mechanisms specifically involved in human UTI. Capitalizing on the advances in molecular pathogenesis research by translating these findings will help develop better clinical strategies for prevention and management of UTIs.

  • Role of phase variation of type 1 fimbriae in a Uropathogenic Escherichia Coli cystitis isolate during urinary tract infection.
    Infection and immunity, 2006
    Co-Authors: Jennifer A. Snyder, Amanda L. Lloyd, C. Virginia Lockatell, David E. Johnson, Harry L. T. Mobley
    Abstract:

    Type 1 fimbrial phase-locked mutants of Uropathogenic Escherichia Coli cystitis isolate F11 were used to assess the role of the invertible element during urinary tract infection. Compared to the wild type, the phase-locked off mutant was attenuated, and constitutive production of type 1 fimbriae by the phase-locked on mutant did not provide a competitive advantage.

Mark A. Schembri - One of the best experts on this subject based on the ideXlab platform.

  • ‘Omic’ Approaches to Study Uropathogenic Escherichia Coli Virulence
    Trends in microbiology, 2017
    Co-Authors: Danilo Gomes Moriel, Minh-duy Phan, Benjamin L. Schulz, Timothy J. Kidd, Scott A. Beatson, Mark A. Schembri
    Abstract:

    Uropathogenic Escherichia Coli (UPEC) is a pathogen of major significance to global human health and is strongly associated with rapidly increasing antibiotic resistance. UPEC is the primary cause of urinary tract infection (UTI), a disease that involves a complicated pathogenic pathway of extracellular and intracellular lifestyles during interaction with the host. The application of multiple ‘omic’ technologies, including genomics, transcriptomics, proteomics, and metabolomics, has provided enormous knowledge to our understanding of UPEC biology. Here we outline this progress and present a view for future developments using these exciting forefront technologies to fully comprehend UPEC pathogenesis in the context of infection.

  • Uropathogenic Escherichia Coli virulence and innate immune responses during urinary tract infection
    Current opinion in microbiology, 2013
    Co-Authors: Glen C. Ulett, Makrina Totsika, Kolja Schaale, Alison J. Carey, Matthew J. Sweet, Mark A. Schembri
    Abstract:

    Urinary tract infections (UTI) are among the most common infectious diseases of humans and are the most common nosocomial infections in the developed world. It is estimated that 40-50% of women and 5% of men will develop a UTI in their lifetime, and UTI accounts for more than 1 million hospitalizations and $1.6 billion in medical expenses each year in the USA. Uropathogenic Escherichia Coli (UPEC) is the primary cause of UTI. This review presents an overview of recent discoveries related to the primary virulence factors of UPEC and major innate immune responses to infection of the lower urinary tract. New and emerging themes in UPEC research are discussed in the context of the interface between host and pathogen.

Isak Demirel - One of the best experts on this subject based on the ideXlab platform.

  • Impact of Proinflammatory Cytokines on the Virulence of Uropathogenic Escherichia Coli.
    Frontiers in microbiology, 2019
    Co-Authors: Ulrik Engelsöy, Ignacio Rangel, Isak Demirel
    Abstract:

    The effect of a urinary tract infection on the host is a well-studied research field. However, how the host immune response affects Uropathogenic Escherichia Coli (CFT073) virulence is less studied. The aim of the present study was to investigate the impact of proinflammatory cytokine exposure on the virulence of Uropathogenic Escherichia Coli. We found that all tested proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8 and IFN-γ) induced an increased CFT073 growth. We also found that biofilm formation and hemolytic activity was reduced in the presence of all proinflammatory cytokines. However, a reduction in siderophore release was only observed in the presence of IL-1β, IL-6 and IL-8. Real time-qPCR showed that all proinflammatory cytokines except TNF-α significantly increased genes associated with the iron acquisition system in CFT073. We also found that the proinflammatory cytokines induced significant changes in type-1 fimbriae, P-fimbriae and gluconeogenetic genes. Furthermore, we also showed, using a C. elegans killing assay that all cytokines decreased the survival of C. elegans worms significantly. Taken together, our findings show that proinflammatory cytokines have the ability to alter the virulence traits of UPEC.

Joel D. Schilling - One of the best experts on this subject based on the ideXlab platform.