Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections
Autor(a) principal: | |
---|---|
Data de Publicação: | 2022 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/134990 |
Resumo: | Bone and implant-related infections caused by Staphylococcus aureus, including methicillin-resistant strains, remains one of the main concerns in modern orthopedic surgery being considered a significant cause of morbidity and mortality worldwide. The rapid increase of S. aureus antimicrobial resistance together with their impact in healthcare, highlights the urgent need of alternative therapeutic compounds. We have recently demonstrated that novel alkylaminophenols (NiPharmins) are promising effective antibacterial agents against several multi-resistant Gram-positive bacteria, including S. aureus. Herein, we evaluated the ability of NiPharmins to induce antimicrobial resistance, its antibiofilm capacity, and the antimicrobial activity of NiPharmin-derived mesoporous silica nanoparticles (MSNs). S. aureus isogenic clones were continuously propagated in vitro without and under a NiPharmin and rifampicin (proof-of-concept) sub-inhibitory concentrations (MIC). Phenotypic tests, coupled with whole genome sequencing were used to assess the putative acquisition of resistance. Regarding antibiofilm capacity, the MIC and biomass of the biofilm was determined. The antimicrobial activity of NiPharmin derivatives was also evaluated. For NiPharmin, the MIC remained unchanged (0.488 μg/mL) during the whole assay, confirmed by comparative genomic analysis between isogenic clones propagated under pressure versus the original isogenic clone, where no resistance-associated mutations were found. This behavior highly contrasts with rifampicin, for which resistant clones started to appear soon after the 2nd passage, reaching MICs up to 4000-fold higher for some clones at the end of the assay. Multiple mutations were observed on the rpoB gene, which are known to be associated to differential susceptibilities to rifampicin. NiPharmin has apparently no preventive activity against biofilms and lost its antibacterial activity when equipped with a triazole-derived linker, prone for MSN grafting. Overall, the strong antimicrobial activity of NiPharmin together with its low toxicity and apparent lack of potential to induce antimicrobial resistance makes this compound a promising therapeutic alternative for the prevention of S. aureus infections. |
id |
RCAP_59e5d030672ecaa8e05ebb60d5617344 |
---|---|
oai_identifier_str |
oai:run.unl.pt:10362/134990 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infectionsStaphylococcus aureusAntimicrobial resistanceNiPharminIn vitro Selective PressureWhole Genome SequencingDomínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e TecnologiasBone and implant-related infections caused by Staphylococcus aureus, including methicillin-resistant strains, remains one of the main concerns in modern orthopedic surgery being considered a significant cause of morbidity and mortality worldwide. The rapid increase of S. aureus antimicrobial resistance together with their impact in healthcare, highlights the urgent need of alternative therapeutic compounds. We have recently demonstrated that novel alkylaminophenols (NiPharmins) are promising effective antibacterial agents against several multi-resistant Gram-positive bacteria, including S. aureus. Herein, we evaluated the ability of NiPharmins to induce antimicrobial resistance, its antibiofilm capacity, and the antimicrobial activity of NiPharmin-derived mesoporous silica nanoparticles (MSNs). S. aureus isogenic clones were continuously propagated in vitro without and under a NiPharmin and rifampicin (proof-of-concept) sub-inhibitory concentrations (MIC). Phenotypic tests, coupled with whole genome sequencing were used to assess the putative acquisition of resistance. Regarding antibiofilm capacity, the MIC and biomass of the biofilm was determined. The antimicrobial activity of NiPharmin derivatives was also evaluated. For NiPharmin, the MIC remained unchanged (0.488 μg/mL) during the whole assay, confirmed by comparative genomic analysis between isogenic clones propagated under pressure versus the original isogenic clone, where no resistance-associated mutations were found. This behavior highly contrasts with rifampicin, for which resistant clones started to appear soon after the 2nd passage, reaching MICs up to 4000-fold higher for some clones at the end of the assay. Multiple mutations were observed on the rpoB gene, which are known to be associated to differential susceptibilities to rifampicin. NiPharmin has apparently no preventive activity against biofilms and lost its antibacterial activity when equipped with a triazole-derived linker, prone for MSN grafting. Overall, the strong antimicrobial activity of NiPharmin together with its low toxicity and apparent lack of potential to induce antimicrobial resistance makes this compound a promising therapeutic alternative for the prevention of S. aureus infections.As infeções ósseas e associadas a implantes causadas por Staphylococcus aureus continuam a ser uma das principais preocupações na cirurgia ortopédica, sendo considerada uma causa significativa de mortalidade em todo o mundo. O rápido aumento da resistência antimicrobiana, juntamente com o seu impacto na área da saúde, destaca a necessidade urgente de compostos terapêuticos alternativos. Recentemente, demonstrámos que novos alquilaminofenóis (NiPharmins) são promissores agentes antibacterianos eficazes contra várias bactérias Gram-positivas multirresistentes. Aqui, avaliamos a capacidade de NiPharmins em induzir resistência antimicrobiana, a sua capacidade antibiofilme e atividade antimicrobiana das nanopartículas de sílica mesoporosas derivadas de NiPharmin (MSNs). Os clones isogénicos de S. aureus foram propagados continuamente in vitro sem e sob uma concentração sub-inibitória (MIC) de NiPharmin e Rifampicina (prova de conceito). Testes fenotípicos, acoplados à sequenciação total do genoma, foram utilizados para avaliar a aquisição de resistências e identificar os seus mecanismos. Relativamente à capacidade antibiofilme, a MIC e a biomassa dos biofilmes foram determinadas. A atividade antimicrobiana dos derivados de NiPharmin também foi avaliada. Para o NiPharmin, a MIC permaneceu inalterada durante todo o ensaio, confirmando-se por análise genómica comparativa, entre clones isogénicos propagados sob pressão versus o clone isogénico original, onde nenhuma mutação associada à resistência foi encontrada. Contrastando com a rifampicina, para a qual clones resistentes apareceram logo após a 2ª passagem, atingindo MICs 4000 vezes maiores para alguns clones no final do ensaio. Múltiplas mutações foram observadas no gene rpoB, sendo conhecidas por estarem associadas a diferentes suscetibilidades à rifampicina. O NiPharmin, aparentemente, não tem atividade preventiva contra biofilmes e perdeu a sua atividade antibacteriana quando associado às MSNs. A forte atividade antimicrobiana do NiPharmin juntamente com a sua baixa toxicidade e aparente falta de potencial para induzir resistência antimicrobiana, tornao uma alternativa terapêutica promissora para a prevenção de infeções por S. aureus.Nunes, AlexandraSobral, RitaRUNAlves, Bárbara André2022-02-252025-03-04T00:00:00Z2022-02-25T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/134990enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:13:26Zoai:run.unl.pt:10362/134990Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:48:16.940103Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
title |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
spellingShingle |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections Alves, Bárbara André Staphylococcus aureus Antimicrobial resistance NiPharmin In vitro Selective Pressure Whole Genome Sequencing Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
title_short |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
title_full |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
title_fullStr |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
title_full_unstemmed |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
title_sort |
Novel alkylaminophenols as antibacterial agents against Staphylococcus aureus infections |
author |
Alves, Bárbara André |
author_facet |
Alves, Bárbara André |
author_role |
author |
dc.contributor.none.fl_str_mv |
Nunes, Alexandra Sobral, Rita RUN |
dc.contributor.author.fl_str_mv |
Alves, Bárbara André |
dc.subject.por.fl_str_mv |
Staphylococcus aureus Antimicrobial resistance NiPharmin In vitro Selective Pressure Whole Genome Sequencing Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
topic |
Staphylococcus aureus Antimicrobial resistance NiPharmin In vitro Selective Pressure Whole Genome Sequencing Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
description |
Bone and implant-related infections caused by Staphylococcus aureus, including methicillin-resistant strains, remains one of the main concerns in modern orthopedic surgery being considered a significant cause of morbidity and mortality worldwide. The rapid increase of S. aureus antimicrobial resistance together with their impact in healthcare, highlights the urgent need of alternative therapeutic compounds. We have recently demonstrated that novel alkylaminophenols (NiPharmins) are promising effective antibacterial agents against several multi-resistant Gram-positive bacteria, including S. aureus. Herein, we evaluated the ability of NiPharmins to induce antimicrobial resistance, its antibiofilm capacity, and the antimicrobial activity of NiPharmin-derived mesoporous silica nanoparticles (MSNs). S. aureus isogenic clones were continuously propagated in vitro without and under a NiPharmin and rifampicin (proof-of-concept) sub-inhibitory concentrations (MIC). Phenotypic tests, coupled with whole genome sequencing were used to assess the putative acquisition of resistance. Regarding antibiofilm capacity, the MIC and biomass of the biofilm was determined. The antimicrobial activity of NiPharmin derivatives was also evaluated. For NiPharmin, the MIC remained unchanged (0.488 μg/mL) during the whole assay, confirmed by comparative genomic analysis between isogenic clones propagated under pressure versus the original isogenic clone, where no resistance-associated mutations were found. This behavior highly contrasts with rifampicin, for which resistant clones started to appear soon after the 2nd passage, reaching MICs up to 4000-fold higher for some clones at the end of the assay. Multiple mutations were observed on the rpoB gene, which are known to be associated to differential susceptibilities to rifampicin. NiPharmin has apparently no preventive activity against biofilms and lost its antibacterial activity when equipped with a triazole-derived linker, prone for MSN grafting. Overall, the strong antimicrobial activity of NiPharmin together with its low toxicity and apparent lack of potential to induce antimicrobial resistance makes this compound a promising therapeutic alternative for the prevention of S. aureus infections. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-02-25 2022-02-25T00:00:00Z 2025-03-04T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/134990 |
url |
http://hdl.handle.net/10362/134990 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799138084014522368 |