Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice
Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Esch...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal Article |
| Language: | English |
| Published: |
2013
|
| Online Access: | https://hdl.handle.net/10356/101172 http://hdl.handle.net/10220/10994 |
| _version_ | 1811690207117836288 |
|---|---|
| author | Kline, Kimberly A. Guiton, Pascale S. Cusumano, Corinne K. Dodson, Karen W. Han, Zhenfu. Janetka, James W. Henderson, Jeffrey P. Caparon, Michael G. Hultgren, Scott J. |
| author_facet | Kline, Kimberly A. Guiton, Pascale S. Cusumano, Corinne K. Dodson, Karen W. Han, Zhenfu. Janetka, James W. Henderson, Jeffrey P. Caparon, Michael G. Hultgren, Scott J. |
| author_sort | Kline, Kimberly A. |
| collection | NTU |
| description | Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic-resistant uropathogens. |
| first_indexed | 2024-10-01T06:00:19Z |
| format | Journal Article |
| id | ntu-10356/101172 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:00:19Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/1011722022-02-16T16:29:37Z Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice Kline, Kimberly A. Guiton, Pascale S. Cusumano, Corinne K. Dodson, Karen W. Han, Zhenfu. Janetka, James W. Henderson, Jeffrey P. Caparon, Michael G. Hultgren, Scott J. Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic-resistant uropathogens. 2013-07-05T04:36:34Z 2019-12-06T20:34:37Z 2013-07-05T04:36:34Z 2019-12-06T20:34:37Z 2012 2012 Journal Article Guiton, P. S., Cusumano, C. K., Kline, K. A., Dodson, K. W., Han, Z., Janetka, J. W., et al. (2012). Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. Antimicrobial Agents and Chemotherapy, 56(9), 4738-4745. 0066-4804 https://hdl.handle.net/10356/101172 http://hdl.handle.net/10220/10994 10.1128/AAC.00447-12 22733070 en Antimicrobial agents and chemotherapy © 2012 American Society for Microbiology. |
| spellingShingle | Kline, Kimberly A. Guiton, Pascale S. Cusumano, Corinne K. Dodson, Karen W. Han, Zhenfu. Janetka, James W. Henderson, Jeffrey P. Caparon, Michael G. Hultgren, Scott J. Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice |
| title | Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice |
| title_full | Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice |
| title_fullStr | Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice |
| title_full_unstemmed | Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice |
| title_short | Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice |
| title_sort | combinatorial small molecule therapy prevents uropathogenic escherichia coli catheter associated urinary tract infections in mice |
| url | https://hdl.handle.net/10356/101172 http://hdl.handle.net/10220/10994 |
| work_keys_str_mv | AT klinekimberlya combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT guitonpascales combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT cusumanocorinnek combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT dodsonkarenw combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT hanzhenfu combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT janetkajamesw combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT hendersonjeffreyp combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT caparonmichaelg combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice AT hultgrenscottj combinatorialsmallmoleculetherapypreventsuropathogenicescherichiacolicatheterassociatedurinarytractinfectionsinmice |