Urinary tract infections: epidemiology, mechanisms of infection and treatment options (original) (raw)
Stamm, W. E. & Norrby, S. R. Urinary tract infections: disease panorama and challenges. J. Infect. Dis.183 (Suppl. 1), S1–S4 (2001). PubMed Google Scholar
Schappert, S. M. & Rechtsteiner, E. A. Ambulatory medical care utilization estimates for 2007. Vital Health Stat.13, 1–38 (2011). Google Scholar
Foxman, B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect. Dis. Clin. North Am.28, 1–13 (2014). This paper presents the most recent information about UTIs and their socioeconomic impact. PubMed Google Scholar
Foxman, B. The epidemiology of urinary tract infection. Nature Rev. Urol.7, 653–660 (2010). Google Scholar
Hooton, T. M. Uncomplicated urinary tract infection. New Engl. J. Med.366, 1028–1037 (2012). CASPubMed Google Scholar
Nielubowicz, G. R. & Mobley, H. L. Host–pathogen interactions in urinary tract infection. Nature Rev. Urol.7, 430–441 (2010). This review compares the strategies used by two important uropathogens,E. coliandP. mirabilis, the host response to each pathogen, and the current treatments and therapies to prevent UTIs. CAS Google Scholar
Hannan, T. J. et al. Host–pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol. Rev.36, 616–648 (2012). CASPubMedPubMed Central Google Scholar
Lichtenberger, P. & Hooton, T. M. Complicated urinary tract infections. Curr. Infect. Dis. Rep.10, 499–504 (2008). PubMed Google Scholar
Levison, M. E. & Kaye, D. Treatment of complicated urinary tract infections with an emphasis on drug-resistant Gram-negative uropathogens. Curr. Infect. Dis. Rep.15, 109–115 (2013). PubMed Google Scholar
Lo, E. et al. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals: 2014 update. Infect. Control Hosp. Epidemiol.35, 464–479 (2014). PubMed Google Scholar
Chenoweth, C. E., Gould, C. V. & Saint, S. Diagnosis, management, and prevention of catheter-associated urinary tract infections. Infect. Dis. Clin. North Am.28, 105–119 (2014). PubMed Google Scholar
Kline, K. A., Schwartz, D. J., Lewis, W. G., Hultgren, S. J. & Lewis, A. L. Immune activation and suppression by group B Streptococcus in a murine model of urinary tract infection. Infect. Immun.79, 3588–3595 (2011). CASPubMedPubMed Central Google Scholar
Ronald, A. The etiology of urinary tract infection: traditional and emerging pathogens. Am. J. Med.113 (Suppl. 1A), 14S–19S (2002). PubMed Google Scholar
Fisher, J. F., Kavanagh, K., Sobel, J. D., Kauffman, C. A. & Newman, C. A. Candida urinary tract infection: pathogenesis. Clin. Infect. Dis.52 (Suppl. 6), S437–S451 (2011). PubMed Google Scholar
Chen, Y. H., Ko, W. C. & Hsueh, P. R. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin. Pharmacother.14, 587–596 (2013). This paper highlights the emerging resistance among bacterial pathogens, the problems we face in combating these resistant bacteria and potential effective agents for the treatment of UTIs caused by multidrug-resistant pathogens. PubMed Google Scholar
Jacobsen, S. M., Stickler, D. J., Mobley, H. L. & Shirtliff, M. E. Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis. Clin. Microbiol. Rev.21, 26–59 (2008). CASPubMedPubMed Central Google Scholar
Kostakioti, M., Hultgren, S. J. & Hadjifrangiskou, M. Molecular blueprint of uropathogenic Escherichia coli virulence provides clues toward the development of anti-virulence therapeutics. Virulence3, 592–594 (2012). PubMedPubMed Central Google Scholar
Subashchandranose, S. et al. Host-specific induction of Escherichia coli fitness genes during human urinary tract infection. Proc. Natl Acad. Sci. USA111, 18327–18332 (2014). Google Scholar
Khandelwal, P., Abraham, S. N. & Apodaca, G. Cell biology and physiology of the uroepithelium. Am. J. Physiol. Renal Physiol.297, F1477–F1501 (2009). CASPubMedPubMed Central Google Scholar
Eto, D. S., Jones, T. A., Sundsbak, J. L. & Mulvey, M. A. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog.3, e100 (2007). PubMedPubMed Central Google Scholar
Niveditha, S., Pramodhini, S., Umadevi, S., Kumar, S. & Stephen, S. The isolation and the biofilm formation of uropathogens in the patients with catheter associated urinary tract infections (UTIs). J. Clin. Diagn. Res.6, 1478–1482 (2012). CASPubMedPubMed Central Google Scholar
Jacobsen, S. M. & Shirtliff, M. E. Proteus mirabilis biofilms and catheter-associated urinary tract infections. Virulence2, 460–465 (2011). This paper briefly outlines the steps ofP. mirabiliscrystalline-biofilm formation during CAUTIs. PubMed Google Scholar
Kline, K. A., Dodson, K. W., Caparon, M. G. & Hultgren, S. J. A tale of two pili: assembly and function of pili in bacteria. Trends Microbiol.18, 224–232 (2010). CASPubMedPubMed Central Google Scholar
Wurpel, D. J., Beatson, S. A., Totsika, M., Petty, N. K. & Schembri, M. A. Chaperone–usher fimbriae of Escherichia coli. PLoS ONE8, e52835 (2013). CASPubMedPubMed Central Google Scholar
Waksman, G. & Hultgren, S. J. Structural biology of the chaperone–usher pathway of pilus biogenesis. Nature Rev. Microbiol.7, 765–774 (2009). This review presents the most current, in-depth understanding of how pili are assembled through the chaperone–usher pathway. CAS Google Scholar
Vallet, I., Olson, J. W., Lory, S., Lazdunski, A. & Filloux, A. The chaperone/usher pathways of Pseudomonas aeruginosa: identification of fimbrial gene clusters (cup) and their involvement in biofilm formation. Proc. Natl Acad. Sci. USA98, 6911–6916 (2001). CASPubMed Google Scholar
Chorell, E. et al. Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study. Bioorg. Med. Chem.20, 3128–3142 (2012). CASPubMedPubMed Central Google Scholar
Thanassi, D. G., Saulino, E. T. & Hultgren, S. J. The chaperone/usher pathway: a major terminal branch of the general secretory pathway. Curr. Opin. Microbiol.1, 223–231 (1998). CASPubMed Google Scholar
Piatek, R. et al. Pilicides inhibit the FGL chaperone/usher assisted biogenesis of the Dr fimbrial polyadhesin from uropathogenic Escherichia coli. BMC Microbiol.13, 131 (2013). This paper provides a brief overview of two similar CUP pilus assembly pathways and shows that antivirulence compounds (pilicides) which were originally designed to specifically target one pathway have broad-spectrum activity against both CUP pilus pathways inE. coli. CASPubMedPubMed Central Google Scholar
Dang, H. T. et al. Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives; antibacterial agents with antivirulence activity. Org. Biomol. Chem.12, 1942–1956 (2014). PubMedPubMed Central Google Scholar
Geibel, S., Procko, E., Hultgren, S. J., Baker, D. & Waksman, G. Structural and energetic basis of folded-protein transport by the FimD usher. Nature496, 243–246 (2013). CASPubMedPubMed Central Google Scholar
Wright, K. J. & Hultgren, S. J. Sticky fibers and uropathogenesis: bacterial adhesins in the urinary tract. Future Microbiol.1, 75–87 (2006). CASPubMed Google Scholar
Hadjifrangiskou, M. et al. Transposon mutagenesis identifies uropathogenic Escherichia coli biofilm factors. J. Bacteriol.194, 6195–6205 (2012). CASPubMedPubMed Central Google Scholar
Guiton, P. S. et al. Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. Antimicrob. Agents Chemother.56, 4738–4745 (2012). CASPubMedPubMed Central Google Scholar
Martinez, J. J. & Hultgren, S. J. Requirement of Rho-family GTPases in the invasion of type 1-piliated uropathogenic Escherichia coli. Cell. Microbiol.4, 19–28 (2002). CASPubMed Google Scholar
Song, J. et al. TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proc. Natl Acad. Sci. USA106, 14966–14971 (2009). CASPubMed Google Scholar
Anderson, G. G. et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science301, 105–107 (2003). This is the first paper to describe the intracellular cycle of a uropathogen and its importance for persistance. CASPubMed Google Scholar
Hannan, T. J., Mysorekar, I. U., Hung, C. S., Isaacson-Schmid, M. L. & Hultgren, S. J. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog.6, e1001042 (2010). PubMedPubMed Central Google Scholar
Kostakioti, M., Hadjifrangiskou, M. & Hultgren, S. J. Bacterial biofilms: development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era. Cold Spring Harb. Perspect. Med.3, a010306 (2013). This review details the importance of biofilm formation for the survival and persistance of different pathogens and the threat that represents in clinical settings. In addition, it discusses novel alternative strategies for the prevention of biofilm formation. PubMedPubMed Central Google Scholar
Rosen, D. A., Hooton, T. M., Stamm, W. E., Humphrey, P. A. & Hultgren, S. J. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med.4, e329 (2007). PubMedPubMed Central Google Scholar
Robino, L. et al. Intracellular bacteria in the pathogenesis of Escherichia coli urinary tract infection in children. Clin. Infect. Dis.59, e158–e164 (2014). CASPubMedPubMed Central Google Scholar
Schwartz, D. J., Chen, S. L., Hultgren, S. J. & Seed, P. C. Population dynamics and niche distribution of uropathogenic Escherichia coli during acute and chronic urinary tract infection. Infect. Immun.79, 4250–4259 (2011). CASPubMedPubMed Central Google Scholar
Blango, M. G., Ott, E. M., Erman, A., Veranic, P. & Mulvey, M. A. Forced resurgence and targeting of intracellular uropathogenic Escherichia coli reservoirs. PLoS ONE9, e93327 (2014). PubMedPubMed Central Google Scholar
Rice, J. C. et al. Pyelonephritic Escherichia coli expressing P fimbriae decrease immune response of the mouse kidney. J. Am. Soc. Nephrol.16, 3583–3591 (2005). CASPubMed Google Scholar
Ashkar, A. A., Mossman, K. L., Coombes, B. K., Gyles, C. L. & Mackenzie, R. FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signalling. PLoS Pathog.4, e1000233 (2008). PubMedPubMed Central Google Scholar
Gerlach, G. F., Clegg, S. & Allen, B. L. Identification and characterization of the genes encoding the type-3 and type-1 fimbrial adhesins of Klebsiella pneumoniae. J. Bacteriol.171, 1262–1270 (1989). CASPubMedPubMed Central Google Scholar
Stahlhut, S. G. et al. Comparative structure–function analysis of mannose-specific FimH adhesins from Klebsiella pneumoniae and Escherichia coli. J. Bacteriol.191, 6592–6601 (2009). CASPubMedPubMed Central Google Scholar
Rosen, D. A. et al. Molecular variations in Klebsiella pneumoniae and Escherichia coli FimH affect function and pathogenesis in the urinary tract. Infect. Immun.76, 3346–3356 (2008). CASPubMedPubMed Central Google Scholar
Rosen, D. A. et al. Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect. Immun.76, 3337–3345 (2008). CASPubMedPubMed Central Google Scholar
Murphy, C. N., Mortensen, M. S., Krogfelt, K. A. & Clegg, S. Role of Klebsiella pneumoniae type 1 and type 3 fimbriae in colonizing silicone tubes implanted into the bladders of mice as a model of catheter-associated urinary tract infections. Infect. Immun.81, 3009–3017 (2013). CASPubMedPubMed Central Google Scholar
Struve, C., Bojer, M. & Krogfelt, K. A. Characterization of Klebsiella pneumoniae type 1 fimbriae by detection of phase variation during colonization and infection and impact on virulence. Infect. Immun.76, 4055–4065 (2008). CASPubMedPubMed Central Google Scholar
Armbruster, C. E. & Mobley, H. L. Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis. Nature Rev. Microbiol.10, 743–754 (2012). CAS Google Scholar
Arias, C. A. & Murray, B. E. The rise of the Enterococcus: beyond vancomycin resistance. Nature Rev. Microbiol.10, 266–278 (2012). This is a comprehensive review of the epidemiology, pathogenesis and mechanism of antimicrobial resistance ofEnterococcusspp. This review also outlines howEnterococcusspp. are becoming a challenging nosocomial problem. CAS Google Scholar
Guiton, P. S., Hung, C. S., Hancock, L. E., Caparon, M. G. & Hultgren, S. J. Enterococcal biofilm formation and virulence in an optimized murine model of foreign body-associated urinary tract infections. Infect. Immun.78, 4166–4175 (2010). CASPubMedPubMed Central Google Scholar
Nielsen, H. V. et al. The metal ion-dependent adhesion site motif of the Enterococcus faecalis EbpA pilin mediates pilus function in catheter-associated urinary tract infection. mBio3, e00177-12 (2012). PubMedPubMed Central Google Scholar
Goble, N. M., Clarke, T. & Hammonds, J. C. Histological changes in the urinary bladder secondary to urethral catheterisation. Br. J. Urol.63, 354–357 (1989). CASPubMed Google Scholar
Glahn, B. E. Influence of drainage conditions on mucosal bladder damage by indwelling catheters. I. Pressure study. Scand. J. Urol. Nephrol.22, 87–92 (1988). CASPubMed Google Scholar
Guiton, P. S., Hannan, T. J., Ford, B., Caparon, M. G. & Hultgren, S. J. Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections. Infect. Immun.81, 329–339 (2013). CASPubMedPubMed Central Google Scholar
Flores-Mireles, A. L., Pinkner, J. S., Caparon, M. G. & Hultgren, S. J. EbpA vaccine antibodies block binding of Enterococcus faecalis to fibrinogen to prevent catheter-associated bladder infection in mice. Sci. Transl. Med.6, 254ra127 (2014). This is the first study to dissect the mechanism ofE. faecalisinfection during a CAUTI; this work led to the development of a vaccine that prevents infection in a mouse model of a CAUTI. PubMedPubMed Central Google Scholar
Nielsen, H. V. et al. Pilin and sortase residues critical for endocarditis- and biofilm-associated pilus biogenesis in Enterococcus faecalis. J. Bacteriol.195, 4484–4495 (2013). CASPubMedPubMed Central Google Scholar
Dhakal, B. K. & Mulvey, M. A. The UPEC pore-forming toxin α-hemolysin triggers proteolysis of host proteins to disrupt cell adhesion, inflammatory, and survival pathways. Cell Host Microbe11, 58–69 (2012). CASPubMedPubMed Central Google Scholar
Nagamatsu, K. et al. Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc. Natl Acad. Sci. USA112, E871–E880 (2015). CASPubMed Google Scholar
Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science282, 1494–1497 (1998). CASPubMed Google Scholar
Justice, S. S. & Hunstad, D. A. UPEC hemolysin: more than just for making holes. Cell Host Microbe11, 4–5 (2012). CASPubMedPubMed Central Google Scholar
Hannan, T. J. et al. LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis. Mol. Microbiol.67, 116–128 (2008). CASPubMed Google Scholar
Garcia, T. A., Ventura, C. L., Smith, M. A., Merrell, D. S. & O'Brien, A. D. Cytotoxic necrotizing factor 1 and hemolysin from uropathogenic Escherichia coli elicit different host responses in the murine bladder. Infect. Immun.81, 99–109 (2013). CASPubMedPubMed Central Google Scholar
Landraud, L. et al. E. coli CNF1 toxin: a two-in-one system for host-cell invasion. Int. J. Med. Microbiol.293, 513–518 (2004). CASPubMed Google Scholar
Piteau, M. et al. Lu/BCAM adhesion glycoprotein is a receptor for Escherichia coli cytotoxic necrotizing factor 1 (CNF1). PLoS Pathog.10, e1003884 (2014). PubMedPubMed Central Google Scholar
Doye, A. et al. CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion. Cell111, 553–564 (2002). CASPubMed Google Scholar
Miraglia, A. G. et al. Cytotoxic necrotizing factor 1 prevents apoptosis via the Akt/IκB kinase pathway: role of nuclear factor-κB and Bcl-2. Mol. Biol. Cell18, 2735–2744 (2007). CASPubMedPubMed Central Google Scholar
Cestari, S. E. et al. Molecular detection of HpmA and HlyA hemolysin of uropathogenic Proteus mirabilis. Curr. Microbiol.67, 703–707 (2013). CASPubMed Google Scholar
Alamuri, P. & Mobley, H. L. A novel autotransporter of uropathogenic Proteus mirabilis is both a cytotoxin and an agglutinin. Mol. Microbiol.68, 997–1017 (2008). CASPubMed Google Scholar
Mittal, R., Khandwaha, R. K., Gupta, V., Mittal, P. K. & Harjai, K. Phenotypic characters of urinary isolates of Pseudomonas aeruginosa and their association with mouse renal colonization. Indian J. Med. Res.123, 67–72 (2006). PubMed Google Scholar
Mittal, R., Sharma, S., Chhibber, S. & Harjai, K. Iron dictates the virulence of Pseudomonas aeruginosa in urinary tract infections. J. Biomed. Sci.15, 731–741 (2008). PubMed Google Scholar
Rocha, C. L., Coburn, J., Rucks, E. A. & Olson, J. C. Characterization of Pseudomonas aeruginosa exoenzyme S as a bifunctional enzyme in J774A.1 macrophages. Infect. Immun.71, 5296–5305 (2003). CASPubMedPubMed Central Google Scholar
Cathcart, G. R. et al. Novel inhibitors of the Pseudomonas aeruginosa virulence factor LasB: a potential therapeutic approach for the attenuation of virulence mechanisms in pseudomonal infection. Antimicrob. Agents Chemother.55, 2670–2678 (2011). CASPubMedPubMed Central Google Scholar
Meyers, D. J. et al. In vivo and in vitro toxicity of phospholipase C from Pseudomonas aeruginosa. Toxicon30, 161–169 (1992). CASPubMed Google Scholar
Wargo, M. J. et al. Hemolytic phospholipase C inhibition protects lung function during Pseudomonas aeruginosa infection. Am. J. Respir. Crit. Care Med.184, 345–354 (2011). CASPubMedPubMed Central Google Scholar
Berka, R. M. & Vasil, M. L. Phospholipase C (heat-labile hemolysin) of Pseudomonas aeruginosa: purification and preliminary characterization. J. Bacteriol.152, 239–245 (1982). CASPubMedPubMed Central Google Scholar
Senturk, S., Ulusoy, S., Bosgelmez-Tinaz, G. & Yagci, A. Quorum sensing and virulence of Pseudomonas aeruginosa during urinary tract infections. J. Infect. Dev. Ctries6, 501–507 (2012). CASPubMed Google Scholar
Mittal, R., Aggarwal, S., Sharma, S., Chhibber, S. & Harjai, K. Urinary tract infections caused by Pseudomonas aeruginosa: a mini review. J. Infect. Publ. Health2, 101–111 (2009). Google Scholar
Li, X. et al. Visualization of Proteus mirabilis within the matrix of urease-induced bladder stones during experimental urinary tract infection. Infect. Immun.70, 389–394 (2002). CASPubMedPubMed Central Google Scholar
Gatermann, S., John, J. & Marre, R. Staphylococcus saprophyticus urease: characterization and contribution to uropathogenicity in unobstructed urinary tract infection of rats. Infect. Immun.57, 110–116 (1989). CASPubMedPubMed Central Google Scholar
Podschun, R. & Ullmann, U. Klebsiella spp. as nosocomial pathogens: epidemiology, taxonomy, typing methods, and pathogenicity factors. Clin. Microbiol. Rev.11, 589–603 (1998). CASPubMedPubMed Central Google Scholar
Visca, P. et al. Virulence determinants in Pseudomonas aeruginosa strains from urinary tract infections. Epidemiol. Infect.108, 323–336 (1992). CASPubMedPubMed Central Google Scholar
Griffith, D. P., Musher, D. M. & Itin, C. Urease. The primary cause of infection-induced urinary stones. Invest. Urol.13, 346–350 (1976). CASPubMed Google Scholar
Coker, C., Poore, C. A., Li, X. & Mobley, H. L. Pathogenesis of Proteus mirabilis urinary tract infection. Microbes Infect.2, 1497–1505 (2000). CASPubMed Google Scholar
Kosikowska, P. & Berlicki, L. Urease inhibitors as potential drugs for gastric and urinary tract infections: a patent review. Expert Opin. Ther. Pat.21, 945–957 (2011). CASPubMed Google Scholar
Jones, B. D. & Mobley, H. L. Genetic and biochemical diversity of ureases of Proteus, Providencia, and Morganella species isolated from urinary tract infection. Infect. Immun.55, 2198–2203 (1987). CASPubMedPubMed Central Google Scholar
Stickler, D. J. Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done. J. Intern. Med.276, 120–129 (2014). CASPubMed Google Scholar
Caza, M. & Kronstad, J. W. Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Front. Cell. Infect. Microbiol.3, 80 (2013). PubMedPubMed Central Google Scholar
Garcia, E. C., Brumbaugh, A. R. & Mobley, H. L. Redundancy and specificity of Escherichia coli iron acquisition systems during urinary tract infection. Infect. Immun.79, 1225–1235 (2011). CASPubMedPubMed Central Google Scholar
Watts, R. E. et al. Contribution of siderophore systems to growth and urinary tract colonization of asymptomatic bacteriuria Escherichia coli. Infect. Immun.80, 333–344 (2012). CASPubMedPubMed Central Google Scholar
Valdebenito, M., Crumbliss, A. L., Winkelmann, G. & Hantke, K. Environmental factors influence the production of enterobactin, salmochelin, aerobactin, and yersiniabactin in Escherichia coli strain Nissle 1917. Int. J. Med. Microbiol.296, 513–520 (2006). CASPubMed Google Scholar
Chaturvedi, K. S., Hung, C. S., Crowley, J. R., Stapleton, A. E. & Henderson, J. P. The siderophore yersiniabactin binds copper to protect pathogens during infection. Nature Chem. Biol.8, 731–736 (2012). CAS Google Scholar
Himpsl, S. D. et al. Proteobactin and a yersiniabactin-related siderophore mediate iron acquisition in Proteus mirabilis. Mol. Microbiol.78, 138–157 (2010). CASPubMedPubMed Central Google Scholar
Brumbaugh, A. R., Smith, S. N. & Mobley, H. L. Immunization with the yersiniabactin receptor, FyuA, protects against pyelonephritis in a murine model of urinary tract infection. Infect. Immun.81, 3309–3316 (2013). This investigation uses data from genomic, proteomic and metabolic screens to identify vaccine targets inE. coli., all of which are involved in iron acquisition. Vaccination with several iron receptors during experimental UTIs in mice revealed that these factors were an effective target for the development of vaccines. CASPubMedPubMed Central Google Scholar
Paterson, D. L. Resistance in Gram-negative bacteria: Enterobacteriaceae. Am. J. Infect. Control34, S20–S28 (2006). PubMed Google Scholar
Garau, J. Other antimicrobials of interest in the era of extended-spectrum β-lactamases: fosfomycin, nitrofurantoin and tigecycline. Clin. Microbiol. Infect.14, 198–202 (2008). CASPubMed Google Scholar
Pendleton, J. N., Gorman, S. P. & Gilmore, B. F. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti Infect. Ther.11, 297–308 (2013). CASPubMed Google Scholar
Gupta, K. & Bhadelia, N. Management of urinary tract infections from multidrug-resistant organisms. Infect. Dis. Clin. North Am.28, 49–59 (2014). PubMed Google Scholar
Bradford, P. A. Extended-spectrum β-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin. Microbiol. Rev.14, 933–951 (2001). CASPubMedPubMed Central Google Scholar
Courvalin, P. Vancomycin resistance in Gram-positive cocci. Clin. Infect. Dis.42 (Suppl. 1), S25–S34 (2006). CASPubMed Google Scholar
Zhanel, G. G. et al. Ceftazidime–avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs73, 159–177 (2013). CASPubMed Google Scholar
Livermore, D. M. & Mushtaq, S. Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J. Antimicrob. Chemother.68, 1825–1831 (2013). CASPubMed Google Scholar
Mushtaq, S., Woodford, N., Hope, R., Adkin, R. & Livermore, D. M. Activity of BAL30072 alone or combined with β-lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters. J. Antimicrob. Chemother.68, 1601–1608 (2013). CASPubMed Google Scholar
Asadi Karam, M. R., Oloomi, M., Mahdavi, M., Habibi, M. & Bouzari, S. Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice. Vaccine31, 1210–1216 (2013). CASPubMed Google Scholar
Langermann, S. et al. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis.181, 774–778 (2000). CASPubMed Google Scholar
Langermann, S. et al. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science276, 607–611 (1997). This pivotal study shows that blocking the interaction between the bacterial adhesin and the host receptor through vaccination can prevent UTIs in mice. CASPubMed Google Scholar
Roberts, J. A. et al. Antibody responses and protection from pyelonephritis following vaccination with purified Escherichia coli PapDG protein. J. Urol.171, 1682–1685 (2004). CASPubMedPubMed Central Google Scholar
Savar, N. S. et al. In silico and in vivo studies of truncated forms of flagellin (FliC) of enteroaggregative Escherichia coli fused to FimH from uropathogenic Escherichia coli as a vaccine candidate against urinary tract infections. J. Biotechnol.175, 31–37 (2014). CASPubMed Google Scholar
Li, X. et al. Use of translational fusion of the MrpH fimbrial adhesin-binding domain with the cholera toxin A2 domain, coexpressed with the cholera toxin B subunit, as an intranasal vaccine to prevent experimental urinary tract infection by Proteus mirabilis. Infect. Immun.72, 7306–7310 (2004). CASPubMedPubMed Central Google Scholar
Sivick, K. E. & Mobley, H. L. Waging war against uropathogenic Escherichia coli: winning back the urinary tract. Infect. Immun.78, 568–585 (2010). CASPubMed Google Scholar
O'Hanley, P., Lalonde, G. & Ji, G. Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: efficacy of an α-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis. Infect. Immun.59, 1153–1161 (1991). CASPubMedPubMed Central Google Scholar
Alamuri, P., Eaton, K. A., Himpsl, S. D., Smith, S. N. & Mobley, H. L. Vaccination with proteus toxic agglutinin, a hemolysin-independent cytotoxin in vivo, protects against Proteus mirabilis urinary tract infection. Infect. Immun.77, 632–641 (2009). CASPubMed Google Scholar
Alteri, C. J., Hagan, E. C., Sivick, K. E., Smith, S. N. & Mobley, H. L. Mucosal immunization with iron receptor antigens protects against urinary tract infection. PLoS Pathog.5, e1000586 (2009). PubMedPubMed Central Google Scholar
Nagaya, H., Satoh, H., Kubo, K. & Maki, Y. Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749. J. Pharmacol. Exp. Ther.248, 799–805 (1989). CASPubMed Google Scholar
Sjostrom, J. E., Kuhler, T. & Larsson, H. Basis for the selective antibacterial activity in vitro of proton pump inhibitors against Helicobacter spp. Antimicrob. Agents Chemother.41, 1797–1801 (1997). CASPubMedPubMed Central Google Scholar
Pinkner, J. S. et al. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc. Natl Acad. Sci. USA103, 17897–17902 (2006). CASPubMed Google Scholar
Cusumano, C. K. et al. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci. Transl. Med.3, 109ra115 (2011). This key work uses compounds designed to prevent theE. colitype 1 pilus adhesin from binding the host receptor and demonstrates that these compounds are effective at preventing UTIs in mice. PubMedPubMed Central Google Scholar
Greene, S. E. et al. Pilicide ec240 disrupts virulence circuits in uropathogenic E. coli. mBio5, e02038 (2014). This is the first paper to describe the role of pilicide in transcriptional and translational regulation in UPEC. CASPubMedPubMed Central Google Scholar
Abgottspon, D. et al. Development of an aggregation assay to screen FimH antagonists. J. Microbiol. Methods82, 249–255 (2010). CASPubMed Google Scholar
Klein, T. et al. FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. J. Med. Chem.53, 8627–8641 (2010). CASPubMed Google Scholar
Totsika, M. et al. A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. J. Infect. Dis.208, 921–928 (2013). CASPubMedPubMed Central Google Scholar
Schwartz, D. J. et al. Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation. Proc. Natl Acad. Sci. USA110, 15530–15537 (2013). This study identifies the role of key FimH residues in protein conformation and virulence. CASPubMed Google Scholar
Sokurenko, E. V., Chesnokova, V., Doyle, R. J. & Hasty, D. L. Diversity of the Escherichia coli type 1 fimbrial lectin. Differential binding to mannosides and uroepithelial cells. J. Biol. Chem.272, 17880–17886 (1997). CASPubMed Google Scholar
Weissman, S. J. et al. Differential stability and trade-off effects of pathoadaptive mutations in the Escherichia coli FimH adhesin. Infect. Immun.75, 3548–3555 (2007). CASPubMedPubMed Central Google Scholar
Justice, S. S., Hunstad, D. A., Cegelski, L. & Hultgren, S. J. Morphological plasticity as a bacterial survival strategy. Nature Rev. Microbiol.6, 162–168 (2008). CAS Google Scholar
Horvath, D. J. Jr et al. Morphological plasticity promotes resistance to phagocyte killing of uropathogenic Escherichia coli. Microbes Infect.13, 426–437 (2011). CASPubMed Google Scholar
Danese, P. N., Pratt, L. A., Dove, S. L. & Kolter, R. The outer membrane protein, antigen 43, mediates cell-to-cell interactions within Escherichia coli biofilms. Mol. Microbiol.37, 424–432 (2000). CASPubMed Google Scholar
Lane, M. C., Li, X., Pearson, M. M., Simms, A. N. & Mobley, H. L. Oxygen-limiting conditions enrich for fimbriate cells of uropathogenic Proteus mirabilis and Escherichia coli. J. Bacteriol.191, 1382–1392 (2009). CASPubMed Google Scholar
Yu, H. et al. Elastase LasB of Pseudomonas aeruginosa promotes biofilm formation partly through rhamnolipid-mediated regulation. Can. J. Microbiol.60, 227–235 (2014). CASPubMed Google Scholar
Diggle, S. P. et al. The galactophilic lectin, LecA, contributes to biofilm development in Pseudomonas aeruginosa. Environ. Microbiol.8, 1095–1104 (2006). CASPubMed Google Scholar
Fazli, M. et al. Regulation of biofilm formation in Pseudomonas and Burkholderia species. Environ. Microbiol.16, 1961–1981 (2014). CASPubMed Google Scholar
Wagner, V. E., Li, L. L., Isabella, V. M. & Iglewski, B. H. Analysis of the hierarchy of quorum-sensing regulation in Pseudomonas aeruginosa. Anal. Bioanal. Chem.387, 469–479 (2007). CASPubMed Google Scholar
Kumar, R., Chhibber, S. & Harjai, K. Quorum sensing is necessary for the virulence of Pseudomonas aeruginosa during urinary tract infection. Kidney Int.76, 286–292 (2009). CASPubMed Google Scholar
Justice, S. S., Hunstad, D. A., Seed, P. C. & Hultgren, S. J. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proc. Natl Acad. Sci. USA103, 19884–19889 (2006). CASPubMed Google Scholar
Morgenstein, R. M. & Rather, P. N. Role of the Umo proteins and the Rcs phosphorelay in the swarming motility of the wild type and an O-antigen (waaL) mutant of Proteus mirabilis. J. Bacteriol.194, 669–676 (2012). CASPubMedPubMed Central Google Scholar
Walther-Rasmussen, J. & Hoiby, N. Cefotaximases (CTX-M-ases), an expanding family of extended-spectrum β-lactamases. Can. J. Microbiol.50, 137–165 (2004). CASPubMed Google Scholar
Schwan, W. R. Flagella allow uropathogenic Escherichia coli ascension into murine kidneys. Int. J. Med. Microbiol.298, 441–447 (2008). CASPubMed Google Scholar
Ulett, G. C. et al. Functional analysis of antigen 43 in uropathogenic Escherichia coli reveals a role in long-term persistence in the urinary tract. Infect. Immun.75, 3233–3244 (2007). CASPubMedPubMed Central Google Scholar
Tarkkanen, A. M. et al. Fimbriation, capsulation, and iron-scavenging systems of Klebsiella strains associated with human urinary tract infection. Infect. Immun.60, 1187–1192 (1992). CASPubMedPubMed Central Google Scholar
Podschun, R., Sievers, D., Fischer, A. & Ullmann, U. Serotypes, hemagglutinins, siderophore synthesis, and serum resistance of Klebsiella isolates causing human urinary tract infections. J. Infect. Dis.168, 1415–1421 (1993). CASPubMed Google Scholar
Dumanski, A. J., Hedelin, H., Edin-Liljegren, A., Beauchemin, D. & McLean, R. J. Unique ability of the Proteus mirabilis capsule to enhance mineral growth in infectious urinary calculi. Infect. Immun.62, 2998–3003 (1994). CASPubMedPubMed Central Google Scholar
Cole, S. J., Records, A. R., Orr, M. W., Linden, S. B. & Lee, V. T. Catheter-associated urinary tract infection by Pseudomonas aeruginosa is mediated by exopolysaccharide-independent biofilms. Infect. Immun.82, 2048–2058 (2014). PubMedPubMed Central Google Scholar
Gupta, P., Gupta, R. K. & Harjai, K. Multiple virulence factors regulated by quorum sensing may help in establishment and colonisation of urinary tract by Pseudomonas aeruginosa during experimental urinary tract infection. Indian J. Med. Microbiol.31, 29–33 (2013). CASPubMed Google Scholar
Hell, W., Meyer, H. G. W. & Gatermann, S. G. Cloning of aas, a gene encoding a Staphylococcus saprophyticus surface protein with adhesive and autolytic properties. Mol. Microbiol.29, 871–881 (1998). CASPubMed Google Scholar
Kline, K. A. et al. Characterization of a novel murine model of Staphylococcus saprophyticus urinary tract infection reveals roles for Ssp and SdrI in virulence. Infect. Immun.78, 1943–1951 (2010). CASPubMedPubMed Central Google Scholar