Anthraquinones as Potential Antibiofilm Agents Against Methicillin-Resistant Staphylococcus aureus

Abstract

Biofilms formed by methicillin-resistant Staphylococcus aureus (MRSA) are one of the contributing factors to recurrent nosocomial infection in humans. There is currently no specific treatment targeting on biofilms in clinical trials approved by FDA, and antibiotics remain the primary therapeutic strategy. In this study, two anthraquinone compounds isolated from a rare actinobacterial strain Kitasatospora albolonga R62, 3,8-dihydroxy-l-methylanthraquinon-2-carboxylic acid (1) and 3,6,8-trihydroxy-1-methylanthraquinone-2-carboxylic acid (2), together with their 10 commercial analogs 3–12 were evaluated for antibacterial and antibiofilm activities against MRSA, which led to the discovery of two potential antibiofilm anthraquinone compounds anthraquinone-2-carboxlic acid (6) and rhein (12). The structure-activity relationship analysis of these anthraquinones indicated that the hydroxyl group at the C-2 position of the anthraquinone skeleton played an important role in inhibiting biofilm formation at high concentrations, while the carboxyl group at the same C-2 position had a great influence on the antibacterial activity and biofilm eradication activity. The results of crystal violet and methyl thiazolyl tetrazolium staining assays, as well as scanning electron microscope and confocal scanning laser microscopy imaging of compounds 6 and 12 treatment groups showed that both compounds could disrupt preformed MRSA biofilms possibly by killing or dispersing biofilm cells. RNA-Seq was subsequently used for the preliminary elucidation of the mechanism of biofilm eradication, and the results showed upregulation of phosphate transport-related genes in the overlapping differentially expressed genes of both compound treatment groups. Herein, we propose that anthraquinone compounds 6 and 12 could be considered promising candidates for the development of antibiofilm agents.

Antiplanktonic and Antibiofilm Activity of Rheum palmatum Against Streptococcus oralis and Porphyromonas gingivalis

“…This indicates that the R. palmatum root extract seems to disrupting the biofilms. A disrupting effect on biofilm structures was already detected for anthraquinone-2-carboxlic acid and rhein [ 57 ], both components of R. palmatum .…”

“…In a study with methicillin-resistant Staphylococcus aureus , antibacterial and antibiofilm activity of rhein has been investigated. Rhein showed bactericidal activity (MIC < 200 µg/mL) and antibiofilm activity after 24 h of exposure, a slight biomass reduction has been observed and viable cells within the biofilm have been significantly dispersed [ 57 ]. These results are in line with our findings.…”

Biofilm-Associated Agr and Sar Quorum Sensing Systems of Staphylococcus aureus Are Inhibited by 3-Hydroxybenzoic Acid Derived from Illicium verum

“…There has been a report of conocarpan compound inhibiting biofilm formation in S. aureus (SA-01). 41 Similarly, another study by Song et al 42 evaluated the antibiofilm potentials of anthraquinone-2-carboxylic acid and rhein compounds derived from the Kitasatospora albolonga R62 strain by employing microscopy techniques. Together, we concluded that the methanol extract of I. verum and its constituent compound 3-HBA inhibited biofilm formation and certain other virulence factors of S. aureus .…”

Phytopigment Alizarin Inhibits Multispecies Biofilm Development by Cutibacterium acnes, Staphylococcus aureus, and Candida albicans

“…Anthraquinones are widely used medicinally and industrially as antimalarials, laxatives, dyes, and antimicrobial agents [ 28 ]. Several anthraquinone derivatives, such as alizarin, chrysazin, emodin, purpurin, and quinalizarin, have been shown to have antibiofilm activity against several microbes, such as Streptococcus mutans [ 29 ], S. aureus [ 7 , 30 ], and C. albicans [ 8 ]. Particularly, alizarin has been reported to efficiently inhibit biofilm development by S. aureus [ 7 , 30 ] and C. albicans [ 8 ] under aerobic conditions.…”