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. 2022 Jan 7:12:770657.
doi: 10.3389/fmicb.2021.770657. eCollection 2021.

Small-Molecule Compound SYG-180-2-2 to Effectively Prevent the Biofilm Formation of Methicillin-Resistant Staphylococcus aureus

Lulin Rao  1 , Yaoguang Sheng  2 , Jiao Zhang  1 , Yanlei Xu  3 , Jingyi Yu  4 , Bingjie Wang  4 , Huilin Zhao  4 , Xinyi Wang  4 , Yinjuan Guo  4 , Xiaocui Wu  4 , Zengqiang Song  2 , Fangyou Yu  1   4 , Lingling Zhan  1
Affiliations

Small-Molecule Compound SYG-180-2-2 to Effectively Prevent the Biofilm Formation of Methicillin-Resistant Staphylococcus aureus

Lulin Rao et al. Front Microbiol. .

Abstract

The resistance of methicillin-resistant Staphylococcus aureus (MRSA) has augmented due to the abuse of antibiotics, bringing about difficulties in the treatment of infection especially with the formation of biofilm. Thus, it is essential to develop antimicrobials. Here we synthesized a novel small-molecule compound, which we termed SYG-180-2-2 (C21H16N2OSe), that had antibiofilm activity. The aim of this study was to demonstrate the antibiofilm effect of SYG-180-2-2 against clinical MRSA isolates at a subinhibitory concentration (4 μg/ml). In this study, it was showed that significant suppression in biofilm formation occurred with SYG-180-2-2 treatment, the inhibition ranged between 65.0 and 85.2%. Subsequently, confocal laser scanning microscopy and a bacterial biofilm metabolism activity assay further demonstrated that SYG-180-2-2 could suppress biofilm. Additionally, SYG-180-2-2 reduced bacterial adhesion and polysaccharide intercellular adhesin (PIA) production. It was found that the expression of icaA and other biofilm-related genes were downregulated as evaluated by RT-qPCR. At the same time, icaR and codY were upregulated when biofilms were treated with SYG-180-2-2. Based on the above results, we speculate that SYG-180-2-2 inhibits the formation of biofilm by affecting cell adhesion and the expression of genes related to PIA production. Above all, SYG-180-2-2 had no toxic effects on human normal alveolar epithelial cells BEAS-2B. Collectively, the small-molecule compound SYG-180-2-2 is a safe and effective antibacterial agent for inhibiting MRSA biofilm.

Keywords: MRSA; SYG-180-2-2; biofilm; cell adhesion; icaA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Synthetic process of SYG-180-2-2. 1: N-pivaloyl indoles. 2: N-(1-pivaloyl-1H-indol-7-yl) benzamide. SYG-180-2-2: desired product.
FIGURE 2
FIGURE 2
Nuclear magnetic resonance (NMR) identification of SYG-180-2-2.
FIGURE 3
FIGURE 3
High-resolution mass spectrometry (HRMS) identification of SYG-180-2-2.
FIGURE 4
FIGURE 4
Growth curves of methicillin-resistant Staphylococcus aureus (MRSA) strains treated with SYG-180-2-2. Strains JP5023 and JP4856 were cultured with 4 μg/ml of or without SYG-180-2-2. Trypticase soy broth (TSB) was used as a blank control. Dimethyl sulfoxide (DMSO) was used as a control in order to exclude the influence of solvent on bacterial growth.
FIGURE 5
FIGURE 5
The effect of SYG-180-2-2 on the formation of biofilm. (A) Biofilm formation in a 96-well plate. At OD600, there was a significant difference in the biofilm formation of JP5023 (B) and JP4856 (C) cultured with or without SYG-180-2-2. ****P < 0.0001.
FIGURE 6
FIGURE 6
Biofilm formation was observed by CLSM. JP5023 and JP4856 treated with SYG-180-2-2 (4 μg/ml).
FIGURE 7
FIGURE 7
The effect of subinhibitory concentration of SYG-180-2-2 on the metabolic activity of MRSA strains JP5023 (A) and JP4856 (B) biofilm. **P < 0.01, ***P < 0.001, and ****P < 0.0001.
FIGURE 8
FIGURE 8
Attachment percent of JP5023 (A) and JP4856 (B) explored by attachment assay (the control was set to 100%). *P < 0.05 and **P < 0.01.
FIGURE 9
FIGURE 9
Effect of the subinhibitory concentration of SYG-180-2-2 on MRSA PIA production.
FIGURE 10
FIGURE 10
The effect of MRSA strains with SYG-180-2-2 treatment on biofilm-related gene expression. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.
FIGURE 11
FIGURE 11
The effect of SYG-180-2-2 on BEAS-2B. (A) The activity of different amounts of BEAS-2B with or without SYG-180-2-2 treatment. (B) Microscopic cell morphology.
See this image and copyright information in PMC

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