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Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections

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  • Authors: Valerie P. O’Brien1, Thomas J. Hannan2, Hailyn V. Nielsen3, Scott J. Hultgren4
  • Editors: Matthew A. Mulvey5, Ann E. Stapleton6, David J. Klumpp7
    Affiliations: 1: >Department of Molecular Microbiology, Center for Women’s Infectious Disease Research; 2: Department of Pathology & Immunology, Washington University Medical School, St. Louis, MO 63110; 3: Department of Molecular Microbiology, Center for Women’s Infectious Disease Research; 4: Department of Molecular Microbiology, Center for Women’s Infectious Disease Research; 5: University of Utah, Salt Lake City, UT; 6: University of Washington, Seattle, WA; 7: Northwestern University, Chicago, IL
  • Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
  • Received 17 August 2012 Accepted 23 March 2015 Published 05 February 2016
  • Scott J. Hultgren, [email protected]
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  • Abstract:

    Urinary tract infections (UTI) are among the most common bacterial infections in humans, affecting millions of people every year. UTI cause significant morbidity in women throughout their lifespan, in infant boys, in older men, in individuals with underlying urinary tract abnormalities, and in those that require long-term urethral catheterization, such as patients with spinal cord injuries or incapacitated individuals living in nursing homes. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth, and complications of frequent antimicrobial use including high-level antibiotic resistance and colitis. Uropathogenic (UPEC) cause the vast majority of UTI, but less common pathogens such as and other enterococci frequently take advantage of an abnormal or catheterized urinary tract to cause opportunistic infections. While antibiotic therapy has historically been very successful in controlling UTI, the high rate of recurrence remains a major problem, and many individuals suffer from chronically recurring UTI, requiring long-term prophylactic antibiotic regimens to prevent recurrent UTI. Furthermore, the global emergence of multi-drug resistant UPEC in the past ten years spotlights the need for alternative therapeutic and preventative strategies to combat UTI, including anti-infective drug therapies and vaccines. In this chapter, we review recent advances in the field of UTI pathogenesis, with an emphasis on the identification of promising drug and vaccine targets. We then discuss the development of new UTI drugs and vaccines, highlighting the challenges these approaches face and the need for a greater understanding of urinary tract mucosal immunity.

  • Citation: O’Brien V, Hannan T, Nielsen H, Hultgren S. 2016. Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections. Microbiol Spectrum 4(1):UTI-0013-2012. doi:10.1128/microbiolspec.UTI-0013-2012.


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Urinary tract infections (UTI) are among the most common bacterial infections in humans, affecting millions of people every year. UTI cause significant morbidity in women throughout their lifespan, in infant boys, in older men, in individuals with underlying urinary tract abnormalities, and in those that require long-term urethral catheterization, such as patients with spinal cord injuries or incapacitated individuals living in nursing homes. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth, and complications of frequent antimicrobial use including high-level antibiotic resistance and colitis. Uropathogenic (UPEC) cause the vast majority of UTI, but less common pathogens such as and other enterococci frequently take advantage of an abnormal or catheterized urinary tract to cause opportunistic infections. While antibiotic therapy has historically been very successful in controlling UTI, the high rate of recurrence remains a major problem, and many individuals suffer from chronically recurring UTI, requiring long-term prophylactic antibiotic regimens to prevent recurrent UTI. Furthermore, the global emergence of multi-drug resistant UPEC in the past ten years spotlights the need for alternative therapeutic and preventative strategies to combat UTI, including anti-infective drug therapies and vaccines. In this chapter, we review recent advances in the field of UTI pathogenesis, with an emphasis on the identification of promising drug and vaccine targets. We then discuss the development of new UTI drugs and vaccines, highlighting the challenges these approaches face and the need for a greater understanding of urinary tract mucosal immunity.

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Targeting UPEC virulence factors that are critical for pathogenesis. Uropathogenic (UPEC) elaborate a variety of surface structures and two-component systems that play critical roles in UTI pathogenesis. The stages of pathogenesis, as determined from animal models and clinical data, include initial bladder colonization and the IBC cycle (), the chronic bladder outcomes of quiescent intracellular-reservoir (QIR) formation () and chronic cystitis (), and ureteral ascension and pyelitis/pyelonephritis with increased risk for bacteremia/septicemia. UPEC surface structures that play a role in UTI pathogenesis include lipopolysaccharide (LPS), polysaccharide capsule, flagella, outer-membrane vesicles, pili, non-pilus adhesins, outer-membrane proteins (OMPs), toxins, secretion systems, and TonB-dependent iron-uptake receptors, including siderophore receptors. These virulence components are attractive drug and vaccine candidates.

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
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Models of pilus assembly in Gram-negative and Gram-positive pathogens. , Model of P pilus formation by the chaperone-usher pathway in uropathogenic . After secretion of pilus subunits into the periplasm via the general Sec machinery, periplasmic chaperones () serve as folding templates, providing a beta-sheet that enables proper folding of the pilin subunits into immunoglobulin-like domains, but in a non-conical orientation, in a mechanism called . Assembly and anchoring of the pilus occurs at an outer-membrane pore known as the usher (orange). The pilus-tip adhesin (red) is the first subunit to interact with the usher, via a preferential interaction between the tip adhesin/periplasmic-chaperone complex and the usher N-terminal-periplasmic domain (NTD, ), and this interaction initiates assembly by causing a conformational change in the usher that “unplugs” (Plug, ) the pore and displaces the tip-adhesin subunit/chaperone complex to two C-terminal-usher domains, CTD1 () and CTD2 () ( 50 , 421 , 422 ). The next pilin subunit/chaperone complex then binds to the NTD and if it has an N-terminal extension that is able to complete the immunoglobulin fold of the preceding subunit in a canonical fashion, this provides the free energy to displace the chaperone, in a process called , and drive assembly ( 47 49 , 423 ). In P pili, this occurs repeatedly, incorporating anywhere from hundreds to thousands of PapA major-pilin subunits (green) in the pilus, until PapH (brown) is incorporated into the pilus. PapH is a terminator because it is unable to undergo donor-strand exchange ( 424 ). Small-molecule inhibitors () that disrupt pilus assembly (“pilicides”) or adhesin binding to its receptor (“pilus-adhesin antagonists”) have been identified ( 223 , 237 ). , Model of sortase-mediated assembly of the endocarditis- and biofilm-associated pilus (Ebp pilus) in ( 217 ). Unlike CUP pili in Gram-negative bacteria, sortase-assembled pilus subunits are covalently linked. Pilin subunits are first secreted to the outside of the cell via the general Sec machinery, and are retained in the membrane via a hydrophobic domain within their cell wall-sorting sequence. Sortase C (SrtC, ) cleaves the EbpA () LPETG sequence, resulting in an EbpA-SrtC thioacyl intermediate that is resolved by the EbpC () Lys186 nucleophile. Pilus polymerization occurs when SrtC processes the EbpC LPSTG sequence at the base of a growing, membrane-associated pilus forming a pilus-SrtC intermediate that is resolved by the Lys186 of an incoming EbpC subunit. EbpB () incorporates at the base of a pilus fiber when its Lys179 nucleophile resolves a pilus-SrtC intermediate. Sortase A (SrtA, ) processing of the EbpB LPKTN sequence leads to eventual incorporation of the mature pilus into the cell wall. Sortase inhibitors () may be useful for disrupting the virulence potential of Gram-positive uropathogens.

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
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Prevalence and sites of action of selected uropathogenic (UPEC) virulence factors and their use as candidate vaccine antigens

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
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Selected candidate vaccines targeting uropathogens

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012

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