Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections.
Identifieur interne : 000A10 ( Main/Exploration ); précédent : 000A09; suivant : 000A11Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections.
Auteurs : Hanwen Wei [République populaire de Chine] ; Fei Mao [République populaire de Chine] ; Shuaishuai Ni [République populaire de Chine] ; Feifei Chen [République populaire de Chine] ; Baoli Li [République populaire de Chine] ; Xiaoxia Qiu [République populaire de Chine] ; Linghao Hu [République populaire de Chine] ; Manjiong Wang [République populaire de Chine] ; Xinyu Zheng [République populaire de Chine] ; Jin Zhu [République populaire de Chine] ; Lefu Lan [République populaire de Chine] ; Jian Li [République populaire de Chine]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Antibactériens (), Antibactériens (pharmacologie), Antibactériens (synthèse chimique), Butoxyde de pipéronyle (), Butoxyde de pipéronyle (analogues et dérivés), Butoxyde de pipéronyle (pharmacologie), Découverte de médicament, Humains, Infections à staphylocoques (traitement médicamenteux), Linézolide (pharmacologie), Méticilline (pharmacologie), Oxidoreductases (antagonistes et inhibiteurs), Oxidoreductases (métabolisme), Protéines bactériennes (antagonistes et inhibiteurs), Protéines bactériennes (métabolisme), Relation dose-effet des médicaments, Relation structure-activité, Résistance bactérienne aux médicaments (), Souris, Staphylococcus aureus (), Staphylococcus aureus (enzymologie), Structure moléculaire, Tests de sensibilité microbienne, Vancomycine (pharmacologie).
- MESH :
- analogues et dérivés : Butoxyde de pipéronyle.
- antagonistes et inhibiteurs : Oxidoreductases, Protéines bactériennes.
- enzymologie : Staphylococcus aureus.
- métabolisme : Oxidoreductases, Protéines bactériennes.
- pharmacologie : Antibactériens, Butoxyde de pipéronyle, Linézolide, Méticilline, Vancomycine.
- synthèse chimique : Antibactériens.
- traitement médicamenteux : Infections à staphylocoques.
- Animaux, Antibactériens, Butoxyde de pipéronyle, Découverte de médicament, Humains, Relation dose-effet des médicaments, Relation structure-activité, Résistance bactérienne aux médicaments, Souris, Staphylococcus aureus, Structure moléculaire, Tests de sensibilité microbienne.
English descriptors
- KwdEn :
- Animals, Anti-Bacterial Agents (chemical synthesis), Anti-Bacterial Agents (chemistry), Anti-Bacterial Agents (pharmacology), Bacterial Proteins (antagonists & inhibitors), Bacterial Proteins (metabolism), Dose-Response Relationship, Drug, Drug Discovery, Drug Resistance, Bacterial (drug effects), Humans, Linezolid (pharmacology), Methicillin (pharmacology), Mice, Microbial Sensitivity Tests, Molecular Structure, Oxidoreductases (antagonists & inhibitors), Oxidoreductases (metabolism), Piperonyl Butoxide (analogs & derivatives), Piperonyl Butoxide (chemistry), Piperonyl Butoxide (pharmacology), Staphylococcal Infections (drug therapy), Staphylococcus aureus (drug effects), Staphylococcus aureus (enzymology), Structure-Activity Relationship, Vancomycin (pharmacology).
- MESH :
- chemical , analogs & derivatives : Piperonyl Butoxide.
- chemical , antagonists & inhibitors : Bacterial Proteins, Oxidoreductases.
- chemical , chemical synthesis : Anti-Bacterial Agents.
- chemical , chemistry : Anti-Bacterial Agents, Piperonyl Butoxide.
- chemical , metabolism : Bacterial Proteins, Oxidoreductases.
- chemical , pharmacology : Anti-Bacterial Agents, Linezolid, Methicillin, Piperonyl Butoxide, Vancomycin.
- drug effects : Drug Resistance, Bacterial, Staphylococcus aureus.
- drug therapy : Staphylococcal Infections.
- enzymology : Staphylococcus aureus.
- Animals, Dose-Response Relationship, Drug, Drug Discovery, Humans, Mice, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship.
Abstract
Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.
DOI: 10.1016/j.ejmech.2017.12.090
PubMed: 29328999
Affiliations:
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Le document en format XML
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populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Mao, Fei" sort="Mao, Fei" uniqKey="Mao F" first="Fei" last="Mao">Fei Mao</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Ni, Shuaishuai" sort="Ni, Shuaishuai" uniqKey="Ni S" first="Shuaishuai" last="Ni">Shuaishuai Ni</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Feifei" sort="Chen, Feifei" uniqKey="Chen F" first="Feifei" last="Chen">Feifei Chen</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Li, Baoli" sort="Li, Baoli" uniqKey="Li B" first="Baoli" last="Li">Baoli Li</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Qiu, Xiaoxia" sort="Qiu, Xiaoxia" uniqKey="Qiu X" first="Xiaoxia" last="Qiu">Xiaoxia Qiu</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Linghao" sort="Hu, Linghao" uniqKey="Hu L" first="Linghao" last="Hu">Linghao Hu</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Manjiong" sort="Wang, Manjiong" uniqKey="Wang M" first="Manjiong" last="Wang">Manjiong Wang</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Zheng, Xinyu" sort="Zheng, Xinyu" uniqKey="Zheng X" first="Xinyu" last="Zheng">Xinyu Zheng</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Zhu, Jin" sort="Zhu, Jin" uniqKey="Zhu J" first="Jin" last="Zhu">Jin Zhu</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237</wicri:regionArea><wicri:noRegion>Shanghai 200237</wicri:noRegion></affiliation></author><author><name sortKey="Lan, Lefu" sort="Lan, Lefu" uniqKey="Lan L" first="Lefu" last="Lan">Lefu Lan</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: llan@simm.ac.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Li, Jian" sort="Li, Jian" uniqKey="Li J" first="Jian" last="Li">Jian Li</name><affiliation wicri:level="1"><nlm:affiliation>Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. 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Discovery</term><term>Drug Resistance, Bacterial (drug effects)</term><term>Humans</term><term>Linezolid (pharmacology)</term><term>Methicillin (pharmacology)</term><term>Mice</term><term>Microbial Sensitivity Tests</term><term>Molecular Structure</term><term>Oxidoreductases (antagonists & inhibitors)</term><term>Oxidoreductases (metabolism)</term><term>Piperonyl Butoxide (analogs & derivatives)</term><term>Piperonyl Butoxide (chemistry)</term><term>Piperonyl Butoxide (pharmacology)</term><term>Staphylococcal Infections (drug therapy)</term><term>Staphylococcus aureus (drug effects)</term><term>Staphylococcus aureus (enzymology)</term><term>Structure-Activity Relationship</term><term>Vancomycin (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antibactériens ()</term><term>Antibactériens (pharmacologie)</term><term>Antibactériens (synthèse chimique)</term><term>Butoxyde de pipéronyle ()</term><term>Butoxyde de pipéronyle (analogues et dérivés)</term><term>Butoxyde de pipéronyle (pharmacologie)</term><term>Découverte de médicament</term><term>Humains</term><term>Infections à staphylocoques (traitement médicamenteux)</term><term>Linézolide (pharmacologie)</term><term>Méticilline (pharmacologie)</term><term>Oxidoreductases (antagonistes et inhibiteurs)</term><term>Oxidoreductases (métabolisme)</term><term>Protéines bactériennes (antagonistes et inhibiteurs)</term><term>Protéines bactériennes (métabolisme)</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Résistance bactérienne aux médicaments ()</term><term>Souris</term><term>Staphylococcus aureus ()</term><term>Staphylococcus aureus (enzymologie)</term><term>Structure moléculaire</term><term>Tests de sensibilité microbienne</term><term>Vancomycine (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Piperonyl Butoxide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Bacterial Proteins</term><term>Oxidoreductases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-Bacterial Agents</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Piperonyl Butoxide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Bacterial Proteins</term><term>Oxidoreductases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Linezolid</term><term>Methicillin</term><term>Piperonyl Butoxide</term><term>Vancomycin</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Butoxyde de pipéronyle</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Oxidoreductases</term><term>Protéines bactériennes</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance, Bacterial</term><term>Staphylococcus aureus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Staphylococcal Infections</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Staphylococcus aureus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Staphylococcus aureus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Oxidoreductases</term><term>Protéines bactériennes</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antibactériens</term><term>Butoxyde de pipéronyle</term><term>Linézolide</term><term>Méticilline</term><term>Vancomycine</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antibactériens</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à staphylocoques</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Dose-Response Relationship, Drug</term><term>Drug Discovery</term><term>Humans</term><term>Mice</term><term>Microbial Sensitivity Tests</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antibactériens</term><term>Butoxyde de pipéronyle</term><term>Découverte de médicament</term><term>Humains</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Résistance bactérienne aux médicaments</term><term>Souris</term><term>Staphylococcus aureus</term><term>Structure moléculaire</term><term>Tests de sensibilité microbienne</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H<sub>2</sub>O<sub>2</sub> killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Wei, Hanwen" sort="Wei, Hanwen" uniqKey="Wei H" first="Hanwen" last="Wei">Hanwen Wei</name></noRegion><name sortKey="Chen, Feifei" sort="Chen, Feifei" uniqKey="Chen F" first="Feifei" last="Chen">Feifei Chen</name><name sortKey="Hu, Linghao" sort="Hu, Linghao" uniqKey="Hu L" first="Linghao" last="Hu">Linghao Hu</name><name sortKey="Lan, Lefu" sort="Lan, Lefu" uniqKey="Lan L" first="Lefu" last="Lan">Lefu Lan</name><name sortKey="Li, Baoli" sort="Li, Baoli" uniqKey="Li B" first="Baoli" last="Li">Baoli Li</name><name sortKey="Li, Jian" sort="Li, Jian" uniqKey="Li J" first="Jian" last="Li">Jian Li</name><name sortKey="Mao, Fei" sort="Mao, Fei" uniqKey="Mao F" first="Fei" last="Mao">Fei Mao</name><name sortKey="Ni, Shuaishuai" sort="Ni, Shuaishuai" uniqKey="Ni S" first="Shuaishuai" last="Ni">Shuaishuai Ni</name><name sortKey="Qiu, Xiaoxia" sort="Qiu, Xiaoxia" uniqKey="Qiu X" first="Xiaoxia" last="Qiu">Xiaoxia Qiu</name><name sortKey="Wang, Manjiong" sort="Wang, Manjiong" uniqKey="Wang M" first="Manjiong" last="Wang">Manjiong Wang</name><name sortKey="Zheng, Xinyu" sort="Zheng, Xinyu" uniqKey="Zheng X" first="Xinyu" last="Zheng">Xinyu Zheng</name><name sortKey="Zhu, Jin" sort="Zhu, Jin" uniqKey="Zhu J" first="Jin" last="Zhu">Jin Zhu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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