Chapter 24 : Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections

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Urinary tract infections (UTI) are one of the most common bacterial infections, with roughly eleven-million cases reported in the U.S. each year that cost an estimated $5 billion annually ( ). More than one in every two women will experience at least one UTI in her lifetime, and nearly one in three women will have received antibiotic treatment for a UTI before age 24 ( ). The clinical manifestations of symptomatic UTI include infection-induced inflammation of the urethra (urethritis), urinary bladder (cystitis), and kidneys (pyelonephritis) and are diagnosed by the presence of high levels of bacteria in the urine (bacteriuria) with concomitant symptoms. Symptoms of cystitis include frequent urination, burning sensation and pain during urination (dysuria), suprapubic pain and/or lower abdominal discomfort, and cloudy and/or bloody, foul-smelling urine. Symptoms of pyelonephritis include the presence of bacteriuria and pyuria (white blood cells in the urine) that is accompanied by flank pain and fever, but may or may not include other symptoms of cystitis. The vast majority of UTI manifest as cystitis and urethritis, affecting primarily the lower urinary tract, but this can potentially lead to bacterial ascension to the kidneys and pyelonephritis, particularly in pregnant women, diabetics, and children with vesicoureteral reflux (VUR) ( ). As a result, renal scarring and loss of function is a potentially serious complication of any UTI, particularly in infants, where diagnosis of UTI may be delayed.

Citation: O’Brien V, Hannan T, Nielsen H, Hultgren S. 2017. Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections, p 589-646. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0013-2012
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Figure 1

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.

Citation: O’Brien V, Hannan T, Nielsen H, Hultgren S. 2017. Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections, p 589-646. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0013-2012
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Figure 2

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 () ( ). 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 ( ). 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 ( ). Small-molecule inhibitors () that disrupt pilus assembly (“pilicides”) or adhesin binding to its receptor (“pilus-adhesin antagonists”) have been identified ( ). , Model of sortase-mediated assembly of the endocarditis- and biofilm-associated pilus (Ebp pilus) in ( ). 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.

Citation: O’Brien V, Hannan T, Nielsen H, Hultgren S. 2017. Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections, p 589-646. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0013-2012
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