Anthraquinones as Potential Antibiofilm Agents Against Methicillin-Resistant Staphylococcus aureus

Zhi-Man Song; Jun-Liang Zhang; Kun Zhou; Lu-Ming Yue; Yu Zhang; Chang-Yun Wang; Kai-Ling Wang; Ying Xu

doi:10.3389/fmicb.2021.709826

Anthraquinones as Potential Antibiofilm Agents Against Methicillin-Resistant Staphylococcus aureus

Front Microbiol. 2021 Sep 3:12:709826. doi: 10.3389/fmicb.2021.709826. eCollection 2021.

Authors

Zhi-Man Song^{1

2

3}, Jun-Liang Zhang¹, Kun Zhou¹, Lu-Ming Yue¹, Yu Zhang¹, Chang-Yun Wang^{4

5

6}, Kai-Ling Wang³, Ying Xu¹

Affiliations

¹ Shenzhen Key Laboratory of Marine Bioresource and Eco-Environmental Science, Shenzhen Engineering Laboratory for Marine Algal Biotechnology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.
² Department of Chemistry, The University of Hong Kong, Pokfulam, Hong Kong, China.
³ College of Pharmacy, Institute of Materia Medica, Dali University, Dali, China.
⁴ Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
⁵ Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
⁶ Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China.

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.

Keywords: Kitasatospora albolonga; Pst system; RNA-Seq; anthraquinones; antibiofilm agents; antibiotics.