A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.cbi.2022.110086 http://hdl.handle.net/11449/240649 |
Resumo: | The emergence and spread of multidrug-resistant (MDR) enterococci and other Gram-positive bacteria represents a severe problem due to the lack of effective therapeutic alternatives. Natural products have long been an important source of new antibacterial scaffolds and can play a key role in the current antibiotic crisis. Enterococci are predominantly non-pathogenic gastrointestinal commensal bacteria, but among them, Enterococcus faecalis and Enterococcus faecium represent the species that account for most clinically relevant infections. The emergence of MDR enterococci has reduced the available antibiotic treatment options and highlights the need to develop new antimicrobial compounds. In the search for new hit compounds against MDR Enterococcus spp., natural-derived compounds represent inspiring scaffolds for drug design studies. In this work, the antimicrobial activity of a fully synthetic chalcone derivative (r4MB) was determined on a clinical panel of 34 MDR Gram-positive bacteria, mostly constituted by E. faecalis and E. faecium, along with Staphylococcus spp., amongst others. Compound r4MB showed activity against 100% of the tested strains, with the minimum inhibitory concentration (MIC) in the range of 5–20 μM. The lethal action of the compound was evaluated using different fluorescent-based assays. The compound showed a time-dependent permeabilisation of the membrane of a vancomycin-resistant E. faecalis, detected by the fluorescent probe SYTOX Green, and digital fluorescent microscopy corroborated the spectrofluorimetric analysis within 6 min of incubation. Flow cytometry analysis of the membrane electric potential demonstrated a significant depolarization, confirming the target of the compound towards the bacterial membrane. No cytotoxic haemolysis was observed with mammalian erythrocytes, and a 99% cytotoxic concentration of 118 μM on NCTC cells demonstrated a promising antimicrobial selectivity. In silico studies using SwissADME and ADMETLabs servers suggest that compound r4MB displayed adequate ADME properties, with no alerts for pan-assay interference compounds (PAINS). Future hit-to-lead optimization of this chalcone derivative can contribute to developing a more potent derivative against infections caused by MDR enterococci. |
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A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalisBacteriaChalconesDrugsEnterococcusMultidrug-resistanceTreatmentThe emergence and spread of multidrug-resistant (MDR) enterococci and other Gram-positive bacteria represents a severe problem due to the lack of effective therapeutic alternatives. Natural products have long been an important source of new antibacterial scaffolds and can play a key role in the current antibiotic crisis. Enterococci are predominantly non-pathogenic gastrointestinal commensal bacteria, but among them, Enterococcus faecalis and Enterococcus faecium represent the species that account for most clinically relevant infections. The emergence of MDR enterococci has reduced the available antibiotic treatment options and highlights the need to develop new antimicrobial compounds. In the search for new hit compounds against MDR Enterococcus spp., natural-derived compounds represent inspiring scaffolds for drug design studies. In this work, the antimicrobial activity of a fully synthetic chalcone derivative (r4MB) was determined on a clinical panel of 34 MDR Gram-positive bacteria, mostly constituted by E. faecalis and E. faecium, along with Staphylococcus spp., amongst others. Compound r4MB showed activity against 100% of the tested strains, with the minimum inhibitory concentration (MIC) in the range of 5–20 μM. The lethal action of the compound was evaluated using different fluorescent-based assays. The compound showed a time-dependent permeabilisation of the membrane of a vancomycin-resistant E. faecalis, detected by the fluorescent probe SYTOX Green, and digital fluorescent microscopy corroborated the spectrofluorimetric analysis within 6 min of incubation. Flow cytometry analysis of the membrane electric potential demonstrated a significant depolarization, confirming the target of the compound towards the bacterial membrane. No cytotoxic haemolysis was observed with mammalian erythrocytes, and a 99% cytotoxic concentration of 118 μM on NCTC cells demonstrated a promising antimicrobial selectivity. In silico studies using SwissADME and ADMETLabs servers suggest that compound r4MB displayed adequate ADME properties, with no alerts for pan-assay interference compounds (PAINS). Future hit-to-lead optimization of this chalcone derivative can contribute to developing a more potent derivative against infections caused by MDR enterococci.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Centre for Parasitology and Mycology Instituto Adolfo Lutz, Av. Dr. Arnaldo, 351, 8 andarInstitute of Biosciences Humanities and Exact Sciences São Paulo State University, Rua Cristóvão Colombo 2265Tropical Medicine Institute University of São PauloCentre of Organic Contaminants Instituto Adolfo Lutz, Av. Dr. Arnaldo, 355Centre of Bacteriology Adolfo Lutz Institute, Av. Dr. Arnaldo, 351Neisseria Research Group Molecular Microbiology School of Clinical and Experimental Sciences University of Southampton Faculty of Medicine Southampton General Hospital, SouthamptonInstitute of Biosciences Humanities and Exact Sciences São Paulo State University, Rua Cristóvão Colombo 2265FAPESP: 2009/53989–4FAPESP: 2014/18330–0FAPESP: 2017/50333–7FAPESP: 2018/15083–2FAPESP: 2018/26655-7FAPESP: 2019/11979–4CNPq: 306251/2016–7CNPq: 309957/2019–2CNPq: 429322/2018–6CNPq: 471129/2013–5FAPESP: FAPESP 2021/04464–8Instituto Adolfo LutzUniversidade Estadual Paulista (UNESP)Universidade de São Paulo (USP)Adolfo Lutz InstituteSouthampton General HospitalTempone, Andre GustavoTheodoro, Reinaldo dos Santos [UNESP]Romanelli, Maiara MariaFerreira, Dayana Agnes SantosAmaral, MaiaraAssis, Leticia Ribeiro de [UNESP]Cruz, Lucas Monteiro SantaCosta, Alan RobertoZanella, Rosemeire CoboChristodoulides, MyronRegasini, Luis Octavio [UNESP]Camargo, Carlos Henrique2023-03-01T20:26:49Z2023-03-01T20:26:49Z2022-09-25info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.cbi.2022.110086Chemico-Biological Interactions, v. 365.1872-77860009-2797http://hdl.handle.net/11449/24064910.1016/j.cbi.2022.1100862-s2.0-85135946812Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengChemico-Biological Interactionsinfo:eu-repo/semantics/openAccess2023-03-01T20:26:50Zoai:repositorio.unesp.br:11449/240649Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T17:13:00.624802Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
title |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
spellingShingle |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis Tempone, Andre Gustavo Bacteria Chalcones Drugs Enterococcus Multidrug-resistance Treatment |
title_short |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
title_full |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
title_fullStr |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
title_full_unstemmed |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
title_sort |
A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis |
author |
Tempone, Andre Gustavo |
author_facet |
Tempone, Andre Gustavo Theodoro, Reinaldo dos Santos [UNESP] Romanelli, Maiara Maria Ferreira, Dayana Agnes Santos Amaral, Maiara Assis, Leticia Ribeiro de [UNESP] Cruz, Lucas Monteiro Santa Costa, Alan Roberto Zanella, Rosemeire Cobo Christodoulides, Myron Regasini, Luis Octavio [UNESP] Camargo, Carlos Henrique |
author_role |
author |
author2 |
Theodoro, Reinaldo dos Santos [UNESP] Romanelli, Maiara Maria Ferreira, Dayana Agnes Santos Amaral, Maiara Assis, Leticia Ribeiro de [UNESP] Cruz, Lucas Monteiro Santa Costa, Alan Roberto Zanella, Rosemeire Cobo Christodoulides, Myron Regasini, Luis Octavio [UNESP] Camargo, Carlos Henrique |
author2_role |
author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Instituto Adolfo Lutz Universidade Estadual Paulista (UNESP) Universidade de São Paulo (USP) Adolfo Lutz Institute Southampton General Hospital |
dc.contributor.author.fl_str_mv |
Tempone, Andre Gustavo Theodoro, Reinaldo dos Santos [UNESP] Romanelli, Maiara Maria Ferreira, Dayana Agnes Santos Amaral, Maiara Assis, Leticia Ribeiro de [UNESP] Cruz, Lucas Monteiro Santa Costa, Alan Roberto Zanella, Rosemeire Cobo Christodoulides, Myron Regasini, Luis Octavio [UNESP] Camargo, Carlos Henrique |
dc.subject.por.fl_str_mv |
Bacteria Chalcones Drugs Enterococcus Multidrug-resistance Treatment |
topic |
Bacteria Chalcones Drugs Enterococcus Multidrug-resistance Treatment |
description |
The emergence and spread of multidrug-resistant (MDR) enterococci and other Gram-positive bacteria represents a severe problem due to the lack of effective therapeutic alternatives. Natural products have long been an important source of new antibacterial scaffolds and can play a key role in the current antibiotic crisis. Enterococci are predominantly non-pathogenic gastrointestinal commensal bacteria, but among them, Enterococcus faecalis and Enterococcus faecium represent the species that account for most clinically relevant infections. The emergence of MDR enterococci has reduced the available antibiotic treatment options and highlights the need to develop new antimicrobial compounds. In the search for new hit compounds against MDR Enterococcus spp., natural-derived compounds represent inspiring scaffolds for drug design studies. In this work, the antimicrobial activity of a fully synthetic chalcone derivative (r4MB) was determined on a clinical panel of 34 MDR Gram-positive bacteria, mostly constituted by E. faecalis and E. faecium, along with Staphylococcus spp., amongst others. Compound r4MB showed activity against 100% of the tested strains, with the minimum inhibitory concentration (MIC) in the range of 5–20 μM. The lethal action of the compound was evaluated using different fluorescent-based assays. The compound showed a time-dependent permeabilisation of the membrane of a vancomycin-resistant E. faecalis, detected by the fluorescent probe SYTOX Green, and digital fluorescent microscopy corroborated the spectrofluorimetric analysis within 6 min of incubation. Flow cytometry analysis of the membrane electric potential demonstrated a significant depolarization, confirming the target of the compound towards the bacterial membrane. No cytotoxic haemolysis was observed with mammalian erythrocytes, and a 99% cytotoxic concentration of 118 μM on NCTC cells demonstrated a promising antimicrobial selectivity. In silico studies using SwissADME and ADMETLabs servers suggest that compound r4MB displayed adequate ADME properties, with no alerts for pan-assay interference compounds (PAINS). Future hit-to-lead optimization of this chalcone derivative can contribute to developing a more potent derivative against infections caused by MDR enterococci. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-09-25 2023-03-01T20:26:49Z 2023-03-01T20:26:49Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.cbi.2022.110086 Chemico-Biological Interactions, v. 365. 1872-7786 0009-2797 http://hdl.handle.net/11449/240649 10.1016/j.cbi.2022.110086 2-s2.0-85135946812 |
url |
http://dx.doi.org/10.1016/j.cbi.2022.110086 http://hdl.handle.net/11449/240649 |
identifier_str_mv |
Chemico-Biological Interactions, v. 365. 1872-7786 0009-2797 10.1016/j.cbi.2022.110086 2-s2.0-85135946812 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Chemico-Biological Interactions |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808128774310461440 |