Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis.
Uropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs), with over 100 million UTIs occurring annually throughout the world. Increasing antimicrobial resistance among UPEC limits ambulatory care options, delays effective treatment, and may inc...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4077706?pdf=render |
| _version_ | 1818318516549320704 |
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| author | Carlos C Goller Mehreen Arshad James W Noah Subramaniam Ananthan Carrie W Evans N Miranda Nebane Lynn Rasmussen Melinda Sosa Nichole A Tower E Lucile White Benjamin Neuenswander Patrick Porubsky Brooks E Maki Steven A Rogers Frank Schoenen Patrick C Seed |
| author_facet | Carlos C Goller Mehreen Arshad James W Noah Subramaniam Ananthan Carrie W Evans N Miranda Nebane Lynn Rasmussen Melinda Sosa Nichole A Tower E Lucile White Benjamin Neuenswander Patrick Porubsky Brooks E Maki Steven A Rogers Frank Schoenen Patrick C Seed |
| author_sort | Carlos C Goller |
| collection | DOAJ |
| description | Uropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs), with over 100 million UTIs occurring annually throughout the world. Increasing antimicrobial resistance among UPEC limits ambulatory care options, delays effective treatment, and may increase overall morbidity and mortality from complications such as urosepsis. The polysaccharide capsules of UPEC are an attractive target a therapeutic, based on their importance in defense against the host immune responses; however, the large number of antigenic types has limited their incorporation into vaccine development. The objective of this study was to identify small-molecule inhibitors of UPEC capsule biogenesis. A large-scale screening effort entailing 338,740 compounds was conducted in a cell-based, phenotypic screen for inhibition of capsule biogenesis in UPEC. The primary and concentration-response assays yielded 29 putative inhibitors of capsule biogenesis, of which 6 were selected for further studies. Secondary confirmatory assays identified two highly active agents, named DU003 and DU011, with 50% inhibitory concentrations of 1.0 µM and 0.69 µM, respectively. Confirmatory assays for capsular antigen and biochemical measurement of capsular sugars verified the inhibitory action of both compounds and demonstrated minimal toxicity and off-target effects. Serum sensitivity assays demonstrated that both compounds produced significant bacterial death upon exposure to active human serum. DU011 administration in mice provided near complete protection against a lethal systemic infection with the prototypic UPEC K1 isolate UTI89. This work has provided a conceptually new class of molecules to combat UPEC infection, and future studies will establish the molecular basis for their action along with efficacy in UTI and other UPEC infections. |
| first_indexed | 2024-12-13T09:54:28Z |
| format | Article |
| id | doaj.art-87e084b83fca45db96122f19cf43b049 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T09:54:28Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-87e084b83fca45db96122f19cf43b0492022-12-21T23:51:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e9605410.1371/journal.pone.0096054Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis.Carlos C GollerMehreen ArshadJames W NoahSubramaniam AnanthanCarrie W EvansN Miranda NebaneLynn RasmussenMelinda SosaNichole A TowerE Lucile WhiteBenjamin NeuenswanderPatrick PorubskyBrooks E MakiSteven A RogersFrank SchoenenPatrick C SeedUropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs), with over 100 million UTIs occurring annually throughout the world. Increasing antimicrobial resistance among UPEC limits ambulatory care options, delays effective treatment, and may increase overall morbidity and mortality from complications such as urosepsis. The polysaccharide capsules of UPEC are an attractive target a therapeutic, based on their importance in defense against the host immune responses; however, the large number of antigenic types has limited their incorporation into vaccine development. The objective of this study was to identify small-molecule inhibitors of UPEC capsule biogenesis. A large-scale screening effort entailing 338,740 compounds was conducted in a cell-based, phenotypic screen for inhibition of capsule biogenesis in UPEC. The primary and concentration-response assays yielded 29 putative inhibitors of capsule biogenesis, of which 6 were selected for further studies. Secondary confirmatory assays identified two highly active agents, named DU003 and DU011, with 50% inhibitory concentrations of 1.0 µM and 0.69 µM, respectively. Confirmatory assays for capsular antigen and biochemical measurement of capsular sugars verified the inhibitory action of both compounds and demonstrated minimal toxicity and off-target effects. Serum sensitivity assays demonstrated that both compounds produced significant bacterial death upon exposure to active human serum. DU011 administration in mice provided near complete protection against a lethal systemic infection with the prototypic UPEC K1 isolate UTI89. This work has provided a conceptually new class of molecules to combat UPEC infection, and future studies will establish the molecular basis for their action along with efficacy in UTI and other UPEC infections.http://europepmc.org/articles/PMC4077706?pdf=render |
| spellingShingle | Carlos C Goller Mehreen Arshad James W Noah Subramaniam Ananthan Carrie W Evans N Miranda Nebane Lynn Rasmussen Melinda Sosa Nichole A Tower E Lucile White Benjamin Neuenswander Patrick Porubsky Brooks E Maki Steven A Rogers Frank Schoenen Patrick C Seed Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis. PLoS ONE |
| title | Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis. |
| title_full | Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis. |
| title_fullStr | Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis. |
| title_full_unstemmed | Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis. |
| title_short | Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis. |
| title_sort | lifting the mask identification of new small molecule inhibitors of uropathogenic escherichia coli group 2 capsule biogenesis |
| url | http://europepmc.org/articles/PMC4077706?pdf=render |
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