Nitrofurans: Revival of an “old” drug class in the fight against antibiotic resistance
Identification of these nitrofuran-activating enzymes in E. coli and understanding their biology (physiological functions, regulation of protein expression/action, and enzyme–nitrofuran molecular interaction) would provide useful knowledge to facilitate development of new nitrofuran-based antibacter...
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description | Identification of these nitrofuran-activating enzymes in E. coli and understanding their biology (physiological functions, regulation of protein expression/action, and enzyme–nitrofuran molecular interaction) would provide useful knowledge to facilitate development of new nitrofuran-based antibacterial therapies. [...]in the case of potential low expression of the activating enzyme, structure-based virtual screens with an ultra-large library [14] targeting the expression regulator of the candidate enzyme or targeting the enzyme allosteric site can be employed to seek the adjuvant molecules that up-regulate the enzyme expression or enhance the enzyme activity, respectively; these adjuvant molecules can be used with nitrofuran antibiotics for improved antibacterial potency. Alternatively, rational design of nitrofuran analogs such that they favorably bind to the redox active site of the activation enzyme through in silico enzyme–drug docking simulation, followed by experimental validation, may generate novel nitrofuran candidates that are different from clinically used nitrofuran drugs in the terms of prodrug activation and resistance mechanisms. Perhaps due to the reduced bacterial growth rate caused by the ribE mutation, mutations in this gene have not been reported in E. coli clinical isolates and are unlikely to pose a significant threat to the efficacy of nitrofuran treatment. |
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[...]in the case of potential low expression of the activating enzyme, structure-based virtual screens with an ultra-large library [14] targeting the expression regulator of the candidate enzyme or targeting the enzyme allosteric site can be employed to seek the adjuvant molecules that up-regulate the enzyme expression or enhance the enzyme activity, respectively; these adjuvant molecules can be used with nitrofuran antibiotics for improved antibacterial potency. Alternatively, rational design of nitrofuran analogs such that they favorably bind to the redox active site of the activation enzyme through in silico enzyme–drug docking simulation, followed by experimental validation, may generate novel nitrofuran candidates that are different from clinically used nitrofuran drugs in the terms of prodrug activation and resistance mechanisms. Perhaps due to the reduced bacterial growth rate caused by the ribE mutation, mutations in this gene have not been reported in E. coli clinical isolates and are unlikely to pose a significant threat to the efficacy of nitrofuran treatment.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1009663</identifier><identifier>PMID: 34237108</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Allosteric properties ; Anti-infective agents ; Antibiotic resistance ; Antibiotics ; Antiinfectives and antibacterials ; Biology and Life Sciences ; Biosynthesis ; Care and treatment ; Clinical isolates ; Drug development ; Drug resistance ; Drug resistance in microorganisms ; E coli ; Enzymatic activity ; Enzyme activity ; Enzymes ; Growth rate ; Identification and classification ; Laboratories ; Medicine and Health Sciences ; Molecular interactions ; Mutation ; Nitrofurans ; Pearls ; Protein expression ; Proteins ; Testing ; Urinary tract diseases ; Urinary tract infections ; Urogenital system</subject><ispartof>PLoS pathogens, 2021-07, Vol.17 (7), p.e1009663-e1009663</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Le, Rakonjac. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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[...]in the case of potential low expression of the activating enzyme, structure-based virtual screens with an ultra-large library [14] targeting the expression regulator of the candidate enzyme or targeting the enzyme allosteric site can be employed to seek the adjuvant molecules that up-regulate the enzyme expression or enhance the enzyme activity, respectively; these adjuvant molecules can be used with nitrofuran antibiotics for improved antibacterial potency. Alternatively, rational design of nitrofuran analogs such that they favorably bind to the redox active site of the activation enzyme through in silico enzyme–drug docking simulation, followed by experimental validation, may generate novel nitrofuran candidates that are different from clinically used nitrofuran drugs in the terms of prodrug activation and resistance mechanisms. 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Rakonjac, Jasna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c638t-f878eacc809dcf81e69c823c4d7a508b2a0cb72d5672d08728bf52bcfd075ffa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Allosteric properties</topic><topic>Anti-infective agents</topic><topic>Antibiotic resistance</topic><topic>Antibiotics</topic><topic>Antiinfectives and antibacterials</topic><topic>Biology and Life Sciences</topic><topic>Biosynthesis</topic><topic>Care and treatment</topic><topic>Clinical isolates</topic><topic>Drug development</topic><topic>Drug resistance</topic><topic>Drug resistance in microorganisms</topic><topic>E coli</topic><topic>Enzymatic activity</topic><topic>Enzyme activity</topic><topic>Enzymes</topic><topic>Growth rate</topic><topic>Identification and classification</topic><topic>Laboratories</topic><topic>Medicine and Health Sciences</topic><topic>Molecular interactions</topic><topic>Mutation</topic><topic>Nitrofurans</topic><topic>Pearls</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Testing</topic><topic>Urinary tract diseases</topic><topic>Urinary tract infections</topic><topic>Urogenital system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Le, Vuong Van Hung</creatorcontrib><creatorcontrib>Rakonjac, Jasna</creatorcontrib><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Le, Vuong Van Hung</au><au>Rakonjac, Jasna</au><au>Leong, John M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nitrofurans: Revival of an “old” drug class in the fight against antibiotic resistance</atitle><jtitle>PLoS pathogens</jtitle><date>2021-07-08</date><risdate>2021</risdate><volume>17</volume><issue>7</issue><spage>e1009663</spage><epage>e1009663</epage><pages>e1009663-e1009663</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Identification of these nitrofuran-activating enzymes in E. coli and understanding their biology (physiological functions, regulation of protein expression/action, and enzyme–nitrofuran molecular interaction) would provide useful knowledge to facilitate development of new nitrofuran-based antibacterial therapies. [...]in the case of potential low expression of the activating enzyme, structure-based virtual screens with an ultra-large library [14] targeting the expression regulator of the candidate enzyme or targeting the enzyme allosteric site can be employed to seek the adjuvant molecules that up-regulate the enzyme expression or enhance the enzyme activity, respectively; these adjuvant molecules can be used with nitrofuran antibiotics for improved antibacterial potency. Alternatively, rational design of nitrofuran analogs such that they favorably bind to the redox active site of the activation enzyme through in silico enzyme–drug docking simulation, followed by experimental validation, may generate novel nitrofuran candidates that are different from clinically used nitrofuran drugs in the terms of prodrug activation and resistance mechanisms. 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subjects | Allosteric properties Anti-infective agents Antibiotic resistance Antibiotics Antiinfectives and antibacterials Biology and Life Sciences Biosynthesis Care and treatment Clinical isolates Drug development Drug resistance Drug resistance in microorganisms E coli Enzymatic activity Enzyme activity Enzymes Growth rate Identification and classification Laboratories Medicine and Health Sciences Molecular interactions Mutation Nitrofurans Pearls Protein expression Proteins Testing Urinary tract diseases Urinary tract infections Urogenital system |
title | Nitrofurans: Revival of an “old” drug class in the fight against antibiotic resistance |
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