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.
Highlights
Bacterial biofilms are surface or interphase-attached microbial communities that are encapsulated in self-secreted extracellular matrix comprising largely of proteins, polysaccharides, nucleic acids, and lipids (Costerton et al, 1999; Flemming and Wingender, 2010)
The preliminary screening results of antibiofilm activities of compounds 1 and 2 revealed that compound 1 had a significant effect on decreasing methicillin-resistant S. aureus (MRSA) biofilm formation by >50% at the concentration of 200 μg/ml while its minimum inhibitory concentrations (MICs) value was higher than 200 μg/ml (Figure 2), but compound 2 showed no obvious bactericidal activity or antibiofilm activity at the same concentration
Only anthraquinone-2-carboxlic acid (6) and rhein (12) exhibited bactericidal activity with MIC values lower than 200 μg/ml. Both compounds had a carboxyl group attached to the C-2 position of the anthraquinone skeleton, which is different from other tested anthraquinones
Summary
Bacterial biofilms are surface or interphase-attached microbial communities that are encapsulated in self-secreted extracellular matrix comprising largely of proteins, polysaccharides, nucleic acids, and lipids (Costerton et al, 1999; Flemming and Wingender, 2010). Bacteria growing inside biofilms are more extremely resistant to hostile environment, antimicrobial agents, and mechanical stresses than their planktonic counterparts (Gilbert et al, 2002; Fux et al, 2005; Hoiby et al, 2010, 2011). It is reported that more than 80% of chronic infections are related with the formation of biofilms by pathogens and very difficult to tackle (Potera, 1999; Lebeaux et al, 2013). There is an urgent need to explore new antibiofilm agents that prevent the formation of MRSA biofilms and/or disrupt the preformed biofilms (Brady et al, 2011; Craigen et al, 2011; Kaplan et al, 2012; Ranall et al, 2012; Bjarnsholt et al, 2013; Alves et al, 2014; Bhattacharya et al, 2015)
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