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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Bibliographic Details
Published in:Scientific reports 2020-11, Vol.10 (1), p.19631, Article 19631
Main Authors: 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
Format: Article
Language:English
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
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-76372-z