Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp.
2-aminoimidazole (2-AI) compounds inhibit the formation of bacterial biofilms, disperse preformed biofilms, and re-sensitize multidrug resistant bacteria to antibiotics. 2-AIs have previously been shown to interact with bacterial response regulators, but the mechanism of interaction is still unknown...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-02-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fmolb.2018.00015/full |
| _version_ | 1818138081410154496 |
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| author | Morgan E. Milton Bradley M. Minrovic Danni L. Harris Brian Kang David Jung Caleb P. Lewis Caleb P. Lewis Richele J. Thompson Roberta J. Melander Daina Zeng Christian Melander John Cavanagh John Cavanagh |
| author_facet | Morgan E. Milton Bradley M. Minrovic Danni L. Harris Brian Kang David Jung Caleb P. Lewis Caleb P. Lewis Richele J. Thompson Roberta J. Melander Daina Zeng Christian Melander John Cavanagh John Cavanagh |
| author_sort | Morgan E. Milton |
| collection | DOAJ |
| description | 2-aminoimidazole (2-AI) compounds inhibit the formation of bacterial biofilms, disperse preformed biofilms, and re-sensitize multidrug resistant bacteria to antibiotics. 2-AIs have previously been shown to interact with bacterial response regulators, but the mechanism of interaction is still unknown. Response regulators are one part of two-component systems (TCS). TCSs allow cells to respond to changes in their environment, and are used to trigger quorum sensing, virulence factors, and antibiotic resistance. Drugs that target the TCS signaling process can inhibit pathogenic behavior, making this a potent new therapeutic approach that has not yet been fully exploited. We previously laid the groundwork for the interaction of the Acinetobacter baumannii response regulator BfmR with an early 2-AI derivative. Here, we further investigate the response regulator/2-AI interaction and look at a wider library of 2-AI compounds. By combining molecular modeling with biochemical and cellular studies, we expand on a potential mechanism for interaction between response regulators and 2-AIs. We also establish that Francisella tularensis/novicida, encoding for only three known response regulators, can be a model system to study the interaction between 2-AIs and response regulators. We show that knowledge gained from studying Francisella can be applied to the more complex A. baumannii system, which contains over 50 response regulators. Understanding the impact of 2-AIs on response regulators and their mechanism of interaction will lead to the development of more potent compounds that will serve as adjuvant therapies to broad-range antibiotics. |
| first_indexed | 2024-12-11T10:06:31Z |
| format | Article |
| id | doaj.art-082ce43dccd94bc0a0d952be55b3fb04 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-11T10:06:31Z |
| publishDate | 2018-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-082ce43dccd94bc0a0d952be55b3fb042022-12-22T01:11:54ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2018-02-01510.3389/fmolb.2018.00015338814Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp.Morgan E. Milton0Bradley M. Minrovic1Danni L. Harris2Brian Kang3David Jung4Caleb P. Lewis5Caleb P. Lewis6Richele J. Thompson7Roberta J. Melander8Daina Zeng9Christian Melander10John Cavanagh11John Cavanagh12Discovery Sciences, RTI International, NC, United StatesDepartment of Chemistry, North Carolina State University, Raleigh, NC, United StatesDiscovery Sciences, RTI International, NC, United StatesAgile Sciences, Inc., Raleigh, NC, United StatesAgile Sciences, Inc., Raleigh, NC, United StatesDiscovery Sciences, RTI International, NC, United StatesDepartment of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, United StatesDiscovery Sciences, RTI International, NC, United StatesDepartment of Chemistry, North Carolina State University, Raleigh, NC, United StatesAgile Sciences, Inc., Raleigh, NC, United StatesDepartment of Chemistry, North Carolina State University, Raleigh, NC, United StatesDiscovery Sciences, RTI International, NC, United StatesDepartment of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, United States2-aminoimidazole (2-AI) compounds inhibit the formation of bacterial biofilms, disperse preformed biofilms, and re-sensitize multidrug resistant bacteria to antibiotics. 2-AIs have previously been shown to interact with bacterial response regulators, but the mechanism of interaction is still unknown. Response regulators are one part of two-component systems (TCS). TCSs allow cells to respond to changes in their environment, and are used to trigger quorum sensing, virulence factors, and antibiotic resistance. Drugs that target the TCS signaling process can inhibit pathogenic behavior, making this a potent new therapeutic approach that has not yet been fully exploited. We previously laid the groundwork for the interaction of the Acinetobacter baumannii response regulator BfmR with an early 2-AI derivative. Here, we further investigate the response regulator/2-AI interaction and look at a wider library of 2-AI compounds. By combining molecular modeling with biochemical and cellular studies, we expand on a potential mechanism for interaction between response regulators and 2-AIs. We also establish that Francisella tularensis/novicida, encoding for only three known response regulators, can be a model system to study the interaction between 2-AIs and response regulators. We show that knowledge gained from studying Francisella can be applied to the more complex A. baumannii system, which contains over 50 response regulators. Understanding the impact of 2-AIs on response regulators and their mechanism of interaction will lead to the development of more potent compounds that will serve as adjuvant therapies to broad-range antibiotics.http://journal.frontiersin.org/article/10.3389/fmolb.2018.00015/fullbiofilmsantibiotic resistancetwo-component systemsresponse regulatorsAcinetobacter baumanniiFrancisella |
| spellingShingle | Morgan E. Milton Bradley M. Minrovic Danni L. Harris Brian Kang David Jung Caleb P. Lewis Caleb P. Lewis Richele J. Thompson Roberta J. Melander Daina Zeng Christian Melander John Cavanagh John Cavanagh Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. Frontiers in Molecular Biosciences biofilms antibiotic resistance two-component systems response regulators Acinetobacter baumannii Francisella |
| title | Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. |
| title_full | Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. |
| title_fullStr | Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. |
| title_full_unstemmed | Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. |
| title_short | Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. |
| title_sort | re sensitizing multidrug resistant bacteria to antibiotics by targeting bacterial response regulators characterization and comparison of interactions between 2 aminoimidazoles and the response regulators bfmr from acinetobacter baumannii and qseb from francisella spp |
| topic | biofilms antibiotic resistance two-component systems response regulators Acinetobacter baumannii Francisella |
| url | http://journal.frontiersin.org/article/10.3389/fmolb.2018.00015/full |
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