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Antibiofilm effects of N,O-acetals derived from 2-amino-1,4-naphthoquinone are associated with downregulation of important global virulence regulators in methicillin-resistant Staphylococcus aureus
Despite the existing antibiotics, antimicrobial resistance is a major challenge. Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study...
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| Published in: | Scientific reports 2020-11, Vol.10 (1), p.19631, Article 19631 |
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| creator | Novais, Juliana Silva Carvalho, Mariana Fernandes Ramundo, Mariana Severo Beltrame, Cristiana Ossaille Geraldo, Reinaldo Barros Jordão, Alessandro Kappel Ferreira, Vítor Francisco Castro, Helena Carla Figueiredo, Agnes Marie Sá |
| description | Despite the existing antibiotics, antimicrobial resistance is a major challenge. Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N,O-acetals derived from 2-amino-1,4-naphthoquinone [7a: 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b: 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c: 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c, specially 7b, caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA, spa, hla and psmα3. More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl (7b) in comparison with 2-propynyloxymethyl (7c) enhanced sarA-agr inhibition, decreased fnbA transcripts (positively regulated by sarA) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation. |
| doi_str_mv | 10.1038/s41598-020-76372-z |
| format | article |
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Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N,O-acetals derived from 2-amino-1,4-naphthoquinone [7a: 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b: 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c: 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c, specially 7b, caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA, spa, hla and psmα3. More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl (7b) in comparison with 2-propynyloxymethyl (7c) enhanced sarA-agr inhibition, decreased fnbA transcripts (positively regulated by sarA) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-76372-z</identifier><identifier>PMID: 33184312</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Acetals - chemistry ; Acetals - pharmacology ; Animals ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibacterial activity ; Antibiotics ; Antimicrobial agents ; Antimicrobial resistance ; Autolysis ; Bacterial Proteins - metabolism ; Biofilms ; Biofilms - drug effects ; Cell Line ; Chlorocebus aethiops ; Down-Regulation - drug effects ; Drug development ; Drug resistance ; Drug Resistance, Bacterial ; Hemolysis - drug effects ; Humans ; Materials Testing ; Methicillin ; Methicillin-Resistant Staphylococcus aureus - drug effects ; Methicillin-Resistant Staphylococcus aureus - pathogenicity ; Methicillin-Resistant Staphylococcus aureus - physiology ; Microbial Sensitivity Tests - methods ; Naphthoquinones - chemistry ; Naphthoquinones - pharmacology ; Quinones ; Staphylococcal Infections - drug therapy ; Staphylococcal Infections - microbiology ; Staphylococcus aureus ; Staphylococcus infections ; Vancomycin ; Vero Cells ; Virulence ; Virulence - drug effects</subject><ispartof>Scientific reports, 2020-11, Vol.10 (1), p.19631, Article 19631</ispartof><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c467t-adafd4a24f403178c53eef12cafc5ae243043014e20da969aa1d5c771c0a234c3</citedby><cites>FETCH-LOGICAL-c467t-adafd4a24f403178c53eef12cafc5ae243043014e20da969aa1d5c771c0a234c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2471561540/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2471561540?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33184312$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Novais, Juliana Silva</creatorcontrib><creatorcontrib>Carvalho, Mariana Fernandes</creatorcontrib><creatorcontrib>Ramundo, Mariana Severo</creatorcontrib><creatorcontrib>Beltrame, Cristiana Ossaille</creatorcontrib><creatorcontrib>Geraldo, Reinaldo Barros</creatorcontrib><creatorcontrib>Jordão, Alessandro Kappel</creatorcontrib><creatorcontrib>Ferreira, Vítor Francisco</creatorcontrib><creatorcontrib>Castro, Helena Carla</creatorcontrib><creatorcontrib>Figueiredo, Agnes Marie Sá</creatorcontrib><title>Antibiofilm effects of N,O-acetals derived from 2-amino-1,4-naphthoquinone are associated with downregulation of important global virulence regulators in methicillin-resistant Staphylococcus aureus</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><description>Despite the existing antibiotics, antimicrobial resistance is a major challenge. Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N,O-acetals derived from 2-amino-1,4-naphthoquinone [7a: 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b: 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c: 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c, specially 7b, caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA, spa, hla and psmα3. More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl (7b) in comparison with 2-propynyloxymethyl (7c) enhanced sarA-agr inhibition, decreased fnbA transcripts (positively regulated by sarA) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation.</description><subject>Acetals - chemistry</subject><subject>Acetals - pharmacology</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterial activity</subject><subject>Antibiotics</subject><subject>Antimicrobial agents</subject><subject>Antimicrobial resistance</subject><subject>Autolysis</subject><subject>Bacterial Proteins - metabolism</subject><subject>Biofilms</subject><subject>Biofilms - drug effects</subject><subject>Cell Line</subject><subject>Chlorocebus aethiops</subject><subject>Down-Regulation - drug effects</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Drug Resistance, Bacterial</subject><subject>Hemolysis - drug effects</subject><subject>Humans</subject><subject>Materials Testing</subject><subject>Methicillin</subject><subject>Methicillin-Resistant Staphylococcus aureus - 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Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N,O-acetals derived from 2-amino-1,4-naphthoquinone [7a: 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b: 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c: 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c, specially 7b, caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA, spa, hla and psmα3. More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl (7b) in comparison with 2-propynyloxymethyl (7c) enhanced sarA-agr inhibition, decreased fnbA transcripts (positively regulated by sarA) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>33184312</pmid><doi>10.1038/s41598-020-76372-z</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Scientific reports, 2020-11, Vol.10 (1), p.19631, Article 19631 |
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| source | ProQuest - Publicly Available Content Database; PubMed Central; Free Full-Text Journals in Chemistry; Springer Nature - nature.com Journals - Fully Open Access |
| subjects | Acetals - chemistry Acetals - pharmacology Animals Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibacterial activity Antibiotics Antimicrobial agents Antimicrobial resistance Autolysis Bacterial Proteins - metabolism Biofilms Biofilms - drug effects Cell Line Chlorocebus aethiops Down-Regulation - drug effects Drug development Drug resistance Drug Resistance, Bacterial Hemolysis - drug effects Humans Materials Testing Methicillin Methicillin-Resistant Staphylococcus aureus - drug effects Methicillin-Resistant Staphylococcus aureus - pathogenicity Methicillin-Resistant Staphylococcus aureus - physiology Microbial Sensitivity Tests - methods Naphthoquinones - chemistry Naphthoquinones - pharmacology Quinones Staphylococcal Infections - drug therapy Staphylococcal Infections - microbiology Staphylococcus aureus Staphylococcus infections Vancomycin Vero Cells Virulence Virulence - drug effects |
| title | Antibiofilm effects of N,O-acetals derived from 2-amino-1,4-naphthoquinone are associated with downregulation of important global virulence regulators in methicillin-resistant Staphylococcus aureus |
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